Advertisement
Cell
This journal offers authors two options (open access or subscription) to publish research

Adapting the proteostasis capacity to sustain brain healthspan

  • Claudio Hetz
    Correspondence
    Corresponding author
    Affiliations
    Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile

    Center for Geroscience, Brain Health and Metabolism, Santiago, Chile

    Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile

    Buck Institute for Research on Aging, Novato, CA, USA
    Search for articles by this author
Open ArchivePublished:March 09, 2021DOI:https://doi.org/10.1016/j.cell.2021.02.007

      Summary

      Sustaining neuronal proteostasis during the course of our life is a central aspect required for brain function. The dynamic nature of synaptic composition and abundance is a requisite to drive cognitive and motor processes involving a tight control of many aspects of protein biosynthesis and degradation. Through the concerted action of specialized stress sensors, the proteostasis network monitors and limits the accumulation of damaged, misfolded, or aggregated proteins. These stress pathways signal to the cytosol and nucleus to reprogram gene expression, enabling adaptive programs to recover cell function. During aging, the activity of the proteostasis network declines, which may increase the risk of accumulating abnormal protein aggregates, a hallmark of most neurodegenerative diseases. Here, I discuss emerging concepts illustrating the functional significance of adaptive signaling pathways to normal brain physiology and their contribution to age-related disorders. Pharmacological and gene therapy strategies to intervene and boost proteostasis are expected to extend brain healthspan and ameliorate disease states.

      Introduction

      The complexity of neuronal networks and the diversity of neuronal identities underlie the emergence of higher cognitive functions of the brain, an essential aspect that defines us as human beings. Understanding how the brain works is still one of the major current challenge of science, not only because this organ is composed of dozens of billions of neuronal and glial cells but also because the plastic nature of the nervous system involves the remodeling of synaptic contacts and their abundancy. This complexity is largely amplified at the molecular level, as individual synapses have an average composition of nearly 1,000–3,000 different proteins that can reach hundreds of thousands of protein units in total (
      • Wilhelm B.G.
      • Mandad S.
      • Truckenbrodt S.
      • Kröhnert K.
      • Schäfer C.
      • Rammner B.
      • Koo S.J.
      • Claßen G.A.
      • Krauss M.
      • Haucke V.
      • et al.
      Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins.
      ).
      It is well established that de novo protein synthesis is required to support the persistence of synaptic changes to convert short-term memories into long-term memories (
      • Sossin W.S.
      • Costa-Mattioli M.
      Translational Control in the Brain in Health and Disease.
      ). Neurons exhibit a unique degree of spatial compartmentalization and are able to maintain and remodel their proteomes independently of the cell body. More than 75% of the total volume of a neuron is formed by dendrites that can make thousands of synapses, requiring the transport of membrane-bound cargo and organelles through complex dendritic arborization and very long axons.
      During their extended lifetime, neurons are exposed to several stressful conditions that can disrupt proteostasis. The importance of maintaining the integrity of the proteome to healthspan is illustrated by the fact that most neurodegenerative disorders are characterized by the accumulation of abnormal protein aggregates in the form of soluble oligomers, fibrils, and large protein inclusions (
      • Soto C.
      • Pritzkow S.
      Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases.
      ). Thus, the ability of synapses to preserve their individual characteristics for long time or modify their composition in response to physiological stimuli imposes a tight and persistence challenge to the proteostasis network. In this article, central mechanisms that mediate the adjustment of proteostasis are discussed, in addition to their involvement in normal brain function and neurodegenerative diseases. The implications of these findings for the future development of therapeutic strategies to alleviate disease states and extend brain healthspan are also discussed.

      Main modules of the proteostasis network: a brief overview

      General biochemical theories about protein-folding mechanisms propose that the acquisition of a native conformation is a thermodynamically favorable event where information about the three-dimensional disposition of amino acids is encoded within the primary structure. Although this premise is true for globular and soluble monomeric proteins, the folding of multidomain or transmembrane proteins is not efficient and is assisted by a complex machinery of chaperones, cofactors, quality-control mechanisms, and specific environmental conditions (
      • Balch W.E.
      • Morimoto R.I.
      • Dillin A.
      • Kelly J.W.
      Adapting proteostasis for disease intervention.
      ). During their folding, proteins navigate through a complex energy landscape where nonproductive intermolecular interactions can result in abnormal aggregation, generating metastable conformations (Figure 1). Protein production is a highly error-prone process in many of its steps and involves alterations at the level of transcription, splicing, folding, and translation (
      • Klaips C.L.
      • Jayaraj G.G.
      • Hartl F.U.
      Pathways of cellular proteostasis in aging and disease.
      ). Thus, protein misfolding is a significant process naturally occurring in healthy cells, imposing constant pressure to the proteostasis machinery. These challenges to the integrity of the proteome are further enhanced by the sustained stress generated by aging and disease states associated with the chronic expression of mutant proteins or the spreading of misfolded proteins throughout the brain (
      • Campisi J.
      • Kapahi P.
      • Lithgow G.J.
      • Melov S.
      • Newman J.C.
      • Verdin E.
      From discoveries in ageing research to therapeutics for healthy ageing.
      ).
      In mammals, nearly 2,000 components of the core proteostasis network have been identified, involving the molecular machineries that mediate the synthesis, folding, quality control, and degradation of proteins, in addition to the regulatory pathways that survey and adjust the protein-folding capacity of the cell according to need (stress pathways) (
      • Jayaraj G.G.
      • Hipp M.S.
      • Hartl F.U.
      Functional Modules of the Proteostasis Network.
      ). These adaptive signaling responses temporally modify the function or levels of individual components of the proteostasis network. Supplementary factors are interconnected to the protein production process, including biosynthetic routes that generate amino acids, tRNAs and related components, and pathways regulating the trafficking and targeting of proteins to their final destination. The subcellular compartmentalization of proteostasis also requires specific environmental conditions (such as redox, ions, and metabolites). A detailed description of the generic effector components governing proteostasis is given in excellent reviews (
      • Jayaraj G.G.
      • Hipp M.S.
      • Hartl F.U.
      Functional Modules of the Proteostasis Network.
      ;
      • Sala A.J.
      • Bott L.C.
      • Morimoto R.I.
      Shaping proteostasis at the cellular, tissue, and organismal level.
      ). Here, I focus on the role of the main adaptive signaling pathways in sustaining proteostasis in the context of brain physiology and disease.
      Figure thumbnail gr1
      Figure 1The proteostasis network
      The production of proteins relies on the proteostasis network to synthetize, fold, mature, and target proteins to their final destination, followed by degradation through the UPS. In aged or diseased cells, increase overload of misfolded proteins and aggregates accumulate that can be further form amyloid fibers and large protein inclusions. The proteostasis network is able to modulate the abundancy of all these abnormal species by different mechanisms. Misfolded protein can be degraded by CMA, whereas large aggregates are efficiently degraded by autophagy.

      Signaling pathways to adjust the proteostasis capacity

      Compartmentalization of the proteostasis network ensures a diversity of cellular processes, ranging from the control of energy metabolism by mitochondria to secretion to cell-to-cell communication, among many other functions. Specialized sensing mechanisms have evolved to locally detect fluctuations in proteome integrity at the cytosol and organelles, transmitting information to the cytosol and nucleus to recover proteostasis (
      • Kaushik S.
      • Cuervo A.M.
      Proteostasis and aging.
      ; Figure 2A). Among these cellular reactions, different signaling pathways monitor protein misfolding in the cytosol, endoplasmic reticulum (ER), and mitochondria, in addition to the catabolic activity of lysosomes. The concerted action of various partially overlapping transcription factors orchestrates the upregulation of genes involved in repair programs to balance protein production. This section briefly summarizes essential feedforward mechanisms that adjust proteostasis under stress.
      Figure thumbnail gr2
      Figure 2Signal pathway to adjust proteostasis
      (A) The accumulation of protein aggregates in the cytosol and different cellular organelles activates specific stress-response mechanisms that modulate gene expression to support the restoration of proteostasis or engage cell death programs.
      (B) Summary of the signaling pathways governing the reestablishment of proteostasis under protein-folding stress. Main stress sensors and transcription factors are presented.

      The integrated stress response (ISR)

      Protein translation by ribosomes is highly complex and requires more than 200 accessory factors (
      • Steffen K.K.
      • Dillin A.
      A Ribosomal Perspective on Proteostasis and Aging.
      ). Translation initiation is a critical regulatory step where eukaryotic initiation factor 2 (eIF2) is loaded with guanosine 5′-triphosphate (GTP) by the guanidine exchange factor eIF2B to recognize the 5′ cap structure of the mRNA. This event involves the formation of a ternary complex that includes eIF2 (trimeric protein of α, β, and γ subunit), the methionine initiator tRNA, and GTP. After scanning the mRNA and detecting the initiating AUG, the 60S subunits assemble to generate the 80S ribosome complex (
      • Sossin W.S.
      • Costa-Mattioli M.
      Translational Control in the Brain in Health and Disease.
      ). Then, eIF2B recycles eIF2 by promoting the exchange of GDP for GTP for subsequent rounds of translation initiation.
      Multiple pathways regulate protein synthesis at the level of eIF2α phosphorylation. The ISR is a central intracellular signaling network controlling translation initiation by physiological stimuli and under stress that enables cells and organisms to adapt to a plethora of conditions to sustain healthspan (
      • Costa-Mattioli M.
      • Walter P.
      The integrated stress response: From mechanism to disease.
      ). Conditions that engage the ISR include metabolic requirements, proteostasis defects at the ER (see next section), viral infections, and oxidative stress, among others. The ISR is initiated by the activation of four specialized stress sensors known as PERK (PKR-like ER kinase), GCN2 (general control nondepressible 2), PKR (double-stranded-RNA-dependent kinase), and HRI (heme-regulated inhibitor). These kinases phosphorylate eIF2α at serine 51, blocking protein synthesis by repressing the action of the GTP exchange factor eIF2B by turning eIF2 into a noncompetitive inhibitor (
      • Costa-Mattioli M.
      • Walter P.
      The integrated stress response: From mechanism to disease.
      ; Figure 2B). This event allows the selected translation of mRNAs containing upstream short reading frames (uORFs), highlighting the mRNA encoding for activating of transcription factor 4 (ATF4), which regulates the expression of multiple genes involved in proteostasis control, including chaperones (Box 1), redox balance, autophagy, and amino acid synthesis (
      • Wang M.
      • Kaufman R.J.
      Protein misfolding in the endoplasmic reticulum as a conduit to human disease.
      ).
      Cytosolic chaperone
      The human “chaperome” is formed by nearly 330 chaperones and cochaperones (
      • Jayaraj G.G.
      • Hipp M.S.
      • Hartl F.U.
      Functional Modules of the Proteostasis Network.
      ). Chaperones are the main effectors of the proteostasis network, performing multiple functions to preserve proteome fitness. Certain chaperones can operate as holdases to prevent aggregation by sequestering and isolating misfolded proteins, whereas others catalyze folding, prevent non-native interactions, or regulate quality-control mechanisms to dispose of terminally misfolded proteins for degradation (
      • Hipp M.S.
      • Kasturi P.
      • Hartl F.U.
      The proteostasis network and its decline in ageing.
      ). Chaperones can also extract polypeptides from aggregates to induce refolding or conversely enhance protein inclusion formation to reduce the load of the more toxic soluble oligomers of misfolded proteins. The activity of chaperones is dependent on the interaction with a variety of cochaperones and other cofactors that orchestrate substrate specificity and function (
      • Kampinga H.H.
      • Craig E.A.
      The HSP70 chaperone machinery: J proteins as drivers of functional specificity.
      ). Chaperones are classified by molecular weight into different protein families, including heat shock protein 70 (HSP70), HSP60, HSP90, and small HSPs, among others. Chaperones recognize the exposed hydrophobic amino acids and unstructured polypeptide backbones as universal features of non-native conformations (
      • Hartl F.U.
      • Bracher A.
      • Hayer-Hartl M.
      Molecular chaperones in protein folding and proteostasis.
      ). HSP70 is the best-studied chaperone that participates in virtually all aspects of the life of a protein. HSP70 performs its function in association with a large set of more than 40 dedicated cochaperones consisting of J-domain (HSP40s) proteins and nucleotide exchange factors that regulate the folding cycle (
      • Faust O.
      • Rosenzweig R.
      Structural and Biochemical Properties of Hsp40/Hsp70 Chaperone System.
      ). The HSP90 system is in turn regulated by the tetratricopeptide proteins (TRP) family.
      The kinetics and amplitude of eIF2α phosphorylation are also regulated by two phosphatase complexes that contain the same catalytic core subunit (PP1) but different regulatory subunits, the constitutively expressed CReP and the stress-inducible subunit GADD34 (
      • Pakos-Zebrucka K.
      • Koryga I.
      • Mnich K.
      • Ljujic M.
      • Samali A.
      • Gorman A.M.
      The integrated stress response.
      ). ATF4 regulates the levels of GADD34, mediating a feedforward loop to regulate translation initiation transiently and shut down the ISR. Under prolonged eIF2α phosphorylation, ATF4 triggers cell death by engaging the propapoptotic factor CHOP in addition to inducing the expression of members of the BCL-2 protein family and enhancing reactive oxygen species (ROS) production and the rates of protein synthesis on a stressed cell (
      • Wang M.
      • Kaufman R.J.
      Protein misfolding in the endoplasmic reticulum as a conduit to human disease.
      ).

      The UPR at the ER and mitochondria

      The ER is the first compartment of the secretory pathway, mediating the production of nearly 30% of the total proteome of the cell. Complex systems of chaperones, cofactors, and quality-control mechanisms catalyze the folding and maturation of secretory cargoes (Box 2). Under ER stress, a signaling network is engaged to adjust proteostasis or trigger apoptosis of irreversibly damaged cells, a process known as the unfolded protein response (UPR) (
      • Hetz C.
      • Zhang K.
      • Kaufman R.J.
      Mechanisms, regulation and functions of the unfolded protein response.
      ). Three types of ER-resident sensors govern the UPR, including inositol requiring enzyme 1 alpha (IRE1), activating of transcription (ATF6), and PERK. Activation of these stress transducers is coupled to the folding machinery through regulatory interactions with various ER chaperones. Under resting conditions, the binding of BiP to the luminal domains of IRE1 and PERK maintains these sensors in a monomeric state, whereas ATF6 is retained at the ER (
      • Preissler S.
      • Ron D.
      Early Events in the Endoplasmic Reticulum Unfolded Protein Response.
      ). Under stress, BiP preferably binds to misfolded proteins, allowing UPR sensors to be activated, in addition to allosterically engaging IRE1 activation. Direct recognition of misfolded proteins, in addition to lipids, has also been proposed for UPR sensors based on structural and biochemical studies (
      • Karagöz G.E.
      • Acosta-Alvear D.
      • Walter P.
      The Unfolded Protein Response: Detecting and Responding to Fluctuations in the Protein-Folding Capacity of the Endoplasmic Reticulum.
      ). Other chaperones also regulate the UPR activation and attenuation processes (
      • Hetz C.
      • Zhang K.
      • Kaufman R.J.
      Mechanisms, regulation and functions of the unfolded protein response.
      ). IRE1 is an RNase that signals through splicing of mRNA encoding for the transcription factor X-box-binding protein-1 (XBP1), releasing an intron of 26 nt (
      • Preissler S.
      • Ron D.
      Early Events in the Endoplasmic Reticulum Unfolded Protein Response.
      ). This event shifts the coding reading frame to express a potent transcription factor known as XBP1s, which regulates many genes involved in secretory pathway function. PERK is a central ER stress sensor that is also part of the ISR (
      • Costa-Mattioli M.
      • Walter P.
      The integrated stress response: From mechanism to disease.
      ). Under prolonged ER stress, the UPR triggers apoptosis through the engagement of several complementary mechanisms, involving the expression of ATF4/CHOP, ROS production, calcium signaling, and microRNA (miRNA) (
      • Oakes S.A.
      • Papa F.R.
      The role of endoplasmic reticulum stress in human pathology.
      ). A recent study identified a second transcription factor controlled by eIF2α phosphorylation, QRICH1, that regulates a transcriptional module involved in protein translation and secretory networks (
      • You K.
      • Wang L.
      • Chou C.H.
      • Liu K.
      • Nakata T.
      • Jaiswal A.
      • Yao J.
      • Lefkovith A.
      • Omar A.
      • Perrigoue J.G.
      • et al.
      QRICH1 dictates the outcome of ER stress through transcriptional control of proteostasis.
      ). Under ER stress, ATF6 translocates to the Golgi apparatus, where it is cleaved to release a bZIP transcription factor contained on its cytosolic domain (ATF6f) that translocates to the nucleus to regulate chaperones and ER-associated degradation (ERAD) components (
      • Hetz C.
      • Zhang K.
      • Kaufman R.J.
      Mechanisms, regulation and functions of the unfolded protein response.
      ).
      Protein folding at the ER
      Oxidative protein folding involves the formation of intramolecular disulfide bonds representing one of the most complicated protein-folding problems because of the number possible disulfide-bonded isomers of a protein containing multiple cysteines. The ER and mitochondria are among the few compartments where proteins can acquire disulfide bonds, which are formed (oxidation), but incorrect bonds need to be broken (reduction) or rearranged by isomerization (
      • Ellgaard L.
      • Ruddock L.W.
      The human protein disulphide isomerase family: substrate interactions and functional properties.
      ). These processes are catalyzed by a group of nearly 20 foldases known as protein disulfide isomerases (PDIs). PDI (also known as PDIA1 or P4HB) is the best-studied member of the family. PDI is oxidized by the oxidoreductase Ero1, coupling disulfide bond formation to the reduction of molecular oxygen. In addition to its function as a redox catalyst, PDI has chaperone activity preventing protein aggregation, in addition to serve in quality-control mechanisms (
      • Bulleid N.J.
      Disulfide bond formation in the mammalian endoplasmic reticulum.
      ). The folding process at the ER is highly complex, since protein concentrations are extremely high, and proteins undergo assisted folding and may mature through different modifications, including protein cleavage, glycosylation, GPI anchoring, amino acid isomerization, and protein complex assembly. The main quality-control mechanisms at the ER are mediated by BiP (GRP78), calnexin, calreticulin, GRP94, and two PDIAs, PDI and ERp57 (PDIA3/Grp58) (
      • Ellgaard L.
      • Helenius A.
      Quality control in the endoplasmic reticulum.
      ). The calnexin and calreticulin cycle catalyzes the folding of glycosylated proteins at the ER and is coupled to the physical association to ERp57. Two enzymes mediate the on and off cycle in this chaperone system: glucosidase II, which dissociates the substrate glycoprotein from calnexin/calreticulin, and UDP-glucose:glycoprotein glucosyltransferase, which restarts a new cycle until glycoproteins achieve a native conformation or otherwise are targeted for ER-associated degradation (ERAD) (
      • Ellgaard L.
      • Helenius A.
      Quality control in the endoplasmic reticulum.
      ).
      Protein misfolding at the mitochondria is regulated by the mitochondrial UPR (UPRmt), a pathway that is well described in C. elegans. In this model, the import, folding, and quality control of mitochondrial proteins is regulated by the transcription factor ATFS-1, which is transported to the mitochondrial and rapidly degraded (
      • Anderson N.S.
      • Haynes C.M.
      Folding the Mitochondrial UPR into the Integrated Stress Response.
      ). Under mitochondrial stress, the protein import capacity is attenuated, accumulating ATFS-1 in the cytosol, which translocates to the nucleus to reprogram gene expression and improve mitochondrial function. The pathway is less studied in mammals, where the ISR/UPR transcription factors ATF4 and CHOP are essential players, in addition to ATF5, which controls a variety of genes involved in mitochondrial protein folding, redox control, and detoxification (
      • Anderson N.S.
      • Haynes C.M.
      Folding the Mitochondrial UPR into the Integrated Stress Response.
      ). Two recent studies identified a previously unknown step in sensing mitochondrial damage. The authors reported that mitochondrial dysfunction (membrane depolarization) is detected by the protease OMA1, which is located on the inner mitochondrial membrane and cleaves the protein DELE1 to release a fragment that directly binds and activates the ISR sensor HRI (
      • Fessler E.
      • Eckl E.M.
      • Schmitt S.
      • Mancilla I.A.
      • Meyer-Bender M.F.
      • Hanf M.
      • Philippou-Massier J.
      • Krebs S.
      • Zischka H.
      • Jae L.T.
      A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol.
      ;
      • Guo X.
      • Aviles G.
      • Liu Y.
      • Tian R.
      • Unger B.A.
      • Lin Y.T.
      • Wiita A.P.
      • Xu K.
      • Correia M.A.
      • Kampmann M.
      Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.
      ).

      The HSR

      One of the main pathways involved in adjusting the levels of cytosolic chaperones according to need is the heat shock response (HSR), which is governed by heat shock transcription factor 1 (HSF1) (
      • Gomez-Pastor R.
      • Burchfiel E.T.
      • Thiele D.J.
      Regulation of heat shock transcription factors and their roles in physiology and disease.
      ). In addition to heat stress, many conditions that perturb the stability of the proteome can activate HSF1, including environmental stress or the expression of disease-related mutant genes (
      • Li J.
      • Labbadia J.
      • Morimoto R.I.
      Rethinking HSF1 in Stress, Development, and Organismal Health.
      ). The activation of HSF1 is coupled to the folding machinery through repressive interactions with cytosolic chaperones (i.e., HSP70 and HSP90), which operate as direct stress sensors. Increased levels of misfolded proteins titrate the folding machinery and release HSF1, which spontaneously trimerizes, triggering its activation (
      • Morimoto R.I.
      The heat shock response: systems biology of proteotoxic stress in aging and disease.
      ). Trimeric HSF1 translocates to the nucleus and binds to heat shock elements in the promoters of target genes, allowing the transcription of a variety of chaperones, components of the UPS, and other quality-control components (
      • Sala A.J.
      • Bott L.C.
      • Morimoto R.I.
      Shaping proteostasis at the cellular, tissue, and organismal level.
      ). In addition, various posttranslational modifications turn the activity of HSF1 on or off, including phosphorylation and ubiquitination (
      • Morimoto R.I.
      The heat shock response: systems biology of proteotoxic stress in aging and disease.
      ).

      Autophagy and lysosome biogenesis

      Protein clearance limits the accumulation of abnormal proteins at resting conditions and under stress, determining the steady-state levels of a particular protein. Autophagy is a catabolic process that involves the transport of cytoplasmic constituents into lysosomes for degradation. Autophagic cargoes include cytosolic proteins and membrane-enclosed organelles. Three main types of autophagy have been described: macroautophagy (here referred to as autophagy), chaperone-mediated autophagy (CMA), and microautophagy. During autophagy, double-membrane phagophores expand to engulf their substrates and then fuse with lysosomes to form the autolysosome, where their components are degraded (
      • Levine B.
      • Kroemer G.
      Biological Functions of Autophagy Genes: A Disease Perspective.
      ). The core autophagy machinery is regulated by a family of ATG proteins that orchestrate different steps of the process. In addition to bulk degradation, selective autophagy can degrade misfolded and aggregated proteins, mediated by the adaptor proteins p62/SQM and NBR1 (
      • Scrivo A.
      • Bourdenx M.
      • Pampliega O.
      • Cuervo A.M.
      Selective autophagy as a potential therapeutic target for neurodegenerative disorders.
      ). In contrast, CMA only targets soluble proteins, which are recognized and unfolded by Hsc70 coupled to the lysosomal receptor LAMP2A for lysosome-mediated degradation (
      • Kaushik S.
      • Cuervo A.M.
      The coming of age of chaperone-mediated autophagy.
      ). Microautophagy is a nonselective autophagic pathway that involves internalization of cytosolic cargo through invaginations of the lysosomal membrane. Microautophagy is poorly explored in the context of the brain and may contribute to biosynthetic transport, metabolic adaptation, organelle remodeling, and quality control (
      • Schuck S.
      Microautophagy - distinct molecular mechanisms handle cargoes of many sizes.
      ).
      Lysosomal biogenesis is regulated by transcription factor EB (TFEB), which can bind to the promoter of numerous genes regulating autophagy induction, lysosomal biogenesis, and lysosomal activity through the recognition of specific motifs in the promoter regions (
      • Saftig P.
      • Puertollano R.
      How Lysosomes Sense, Integrate, and Cope with Stress.
      ). Retention of TFEB in the cytosol and the lysosomal membrane under nonstressed conditions is achieved by phosphorylation of specific residues by different signaling pathways (mTOR, AKT, and mitogen-activated protein kinase [MAPK], among others) that promote the binding to the cytosolic chaperone 14-3-3. Dephosphorylation of TFEB under stress conditions allows its activation and translocation to the nucleus. Interestingly, TFEB can also be regulated by the ISR (
      • Saftig P.
      • Puertollano R.
      How Lysosomes Sense, Integrate, and Cope with Stress.
      ), suggesting crosstalk between both pathways.

      Proteostasis control of normal brain function

      Most of the attention in the proteostasis field has been historically focused on neurodegenerative diseases because of the obvious relationship with protein misfolding and aggregation. However, accumulating evidence indicates that the mechanisms that adjust proteostasis also contribute to neuronal physiology, impacting brain development and adult life. In this section, relevant studies are discussed illustrating this emerging concept that will also help explain why dysfunction in the pathways that balance proteostasis underlies the origin of diseases affecting the nervous system.

      Stress responses and neuronal physiology

      The storage of new information requires the modulation in the strength of neuronal connections. Major activity-dependent changes in synaptic function include long-term potentiation (LTP) and long-term depression (LTD), involving stable increases and decreases in the efficacy of synaptic connections, which is coupled to the regulation of new protein synthesis (
      • Sossin W.S.
      • Costa-Mattioli M.
      Translational Control in the Brain in Health and Disease.
      ). Remarkable advances in the field have been made due to the generation of genetically modified mice and small molecules to tune translation initiation. Mice engineered to reduce eIF2α phosphorylation show enhanced LTP, whereas augmentation of eIF2α phosphorylation has the opposite effects (
      • Costa-Mattioli M.
      • Gobert D.
      • Stern E.
      • Gamache K.
      • Colina R.
      • Cuello C.
      • Sossin W.
      • Kaufman R.
      • Pelletier J.
      • Rosenblum K.
      • et al.
      eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory.
      ). Genetic targeting of the ISR kinases PERK, GCN2, or PKR or replacement of serine 51 for alanine in eIF2α enhances long-term memory formation (
      • Costa-Mattioli M.
      • Gobert D.
      • Harding H.
      • Herdy B.
      • Azzi M.
      • Bruno M.
      • Bidinosti M.
      • Ben Mamou C.
      • Marcinkiewicz E.
      • Yoshida M.
      • et al.
      Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2.
      ;
      • Ounallah-Saad H.
      • Sharma V.
      • Edry E.
      • Rosenblum K.
      Genetic or pharmacological reduction of PERK enhances cortical-dependent taste learning.
      ;
      • Stern E.
      • Chinnakkaruppan A.
      • David O.
      • Sonenberg N.
      • Rosenblum K.
      Blocking the eIF2α kinase (PKR) enhances positive and negative forms of cortex-dependent taste memory.
      ;
      • Zhu P.J.
      • Huang W.
      • Kalikulov D.
      • Yoo J.W.
      • Placzek A.N.
      • Stoica L.
      • Zhou H.
      • Bell J.C.
      • Friedlander M.J.
      • Krnjević K.
      • et al.
      Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition.
      ). In addition, PERK deficiency in the forebrain of mice causes repetitive and perseverant behaviors (
      • Trinh M.A.
      • Kaphzan H.
      • Wek R.C.
      • Pierre P.
      • Cavener D.R.
      • Klann E.
      Brain-specific disruption of the eIF2α kinase PERK decreases ATF4 expression and impairs behavioral flexibility.
      ). ISRIB, a small molecule that activates eIF2B and blocks the consequences eIF2α phosphorylation, improves LTP at basal levels, and is associated with better learning and memory capacity in mice (
      • Sidrauski C.
      • Acosta-Alvear D.
      • Khoutorsky A.
      • Vedantham P.
      • Hearn B.R.
      • Li H.
      • Gamache K.
      • Gallagher C.M.
      • Ang K.K.
      • Wilson C.
      • et al.
      Pharmacological brake-release of mRNA translation enhances cognitive memory.
      ). The circuits involved in the control of eIF2α-dependent mRNA translation during memory consolidation were recently mapped to excitatory and somatostatin-expressing inhibitory neurons (
      • Sharma V.
      • Sood R.
      • Khlaifia A.
      • Eslamizade M.J.
      • Hung T.Y.
      • Lou D.
      • Asgarihafshejani A.
      • Lalzar M.
      • Kiniry S.J.
      • Stokes M.P.
      • et al.
      eIF2α controls memory consolidation via excitatory and somatostatin neurons.
      ). ISRIB administration is also able to delay the natural decline of cognitive function during aging (
      • Krukowski K.
      • Nolan A.
      • Frias E.S.
      • Boone M.
      • Ureta G.
      • Grue K.
      • Paladini M.S.
      • Elizarraras E.
      • Delgado L.
      • Bernales S.
      • et al.
      Small molecule cognitive enhancer reverses age-related memory decline in mice.
      ) and improves synaptic plasticity and memory in models of Down syndrome (
      • Zhu P.J.
      • Khatiwada S.
      • Cui Y.
      • Reineke L.C.
      • Dooling S.W.
      • Kim J.J.
      • Li W.
      • Walter P.
      • Costa-Mattioli M.
      Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome.
      ).
      Transcriptional regulation by ATF4 has been also associated with learning and memory and synaptic plasticity, although most available data are not well aligned (
      • Martínez G.
      • Khatiwada S.
      • Costa-Mattioli M.
      • Hetz C.
      ER Proteostasis Control of Neuronal Physiology and Synaptic Function.
      ). ATF4 negatively controls the transcriptional activity of CREB, a central factor tuning neuronal activity. PERK signaling has also been suggested to impact various neuronal populations, regulating neurogenesis in the hippocampus and brain development (
      • Laguesse S.
      • Creppe C.
      • Nedialkova D.D.
      • Prévot P.P.
      • Borgs L.
      • Huysseune S.
      • Franco B.
      • Duysens G.
      • Krusy N.
      • Lee G.
      • et al.
      A Dynamic Unfolded Protein Response Contributes to the Control of Cortical Neurogenesis.
      ), in addition to axon migration and visual pathway development (
      • Cagnetta R.
      • Wong H.H.
      • Frese C.K.
      • Mallucci G.R.
      • Krijgsveld J.
      • Holt C.E.
      Noncanonical Modulation of the eIF2 Pathway Controls an Increase in Local Translation during Neural Wiring.
      ). A recent CRISPR tissue-screening study using brain organoids revealed a key role of ER proteostasis and the UPR in the control of brain volume (
      • Esk C.
      • Lindenhofer D.
      • Haendeler S.
      • Wester R.A.
      • Pflug F.
      • Schroeder B.
      • Bagley J.A.
      • Elling U.
      • Zuber J.
      • von Haeseler A.
      • Knoblich J.A.
      A human tissue screen identifies a regulator of ER secretion as a brain-size determinant.
      ). Although these studies demonstrate that eIF2α is a central point of control of synaptic activity, the exact mechanisms that engage ISR sensors by synaptic-related inputs remain poorly understood.
      Phenotypic screening of conditional knockout mice for XBP1 in the brain uncovered its function in memory formation and synaptic plasticity (
      • Martínez G.
      • Vidal R.L.
      • Mardones P.
      • Serrano F.G.
      • Ardiles A.O.
      • Wirth C.
      • Valdés P.
      • Thielen P.
      • Schneider B.L.
      • Kerr B.
      • et al.
      Regulation of Memory Formation by the Transcription Factor XBP1.
      ). In the context of neurons, XBP1s regulates the expression of a variety of genes related to dendritic function and synaptic activity, including BDNF and GABAergic markers (
      • Hayashi A.
      • Kasahara T.
      • Kametani M.
      • Kato T.
      Attenuated BDNF-induced upregulation of GABAergic markers in neurons lacking Xbp1.
      ;
      • Martínez G.
      • Vidal R.L.
      • Mardones P.
      • Serrano F.G.
      • Ardiles A.O.
      • Wirth C.
      • Valdés P.
      • Thielen P.
      • Schneider B.L.
      • Kerr B.
      • et al.
      Regulation of Memory Formation by the Transcription Factor XBP1.
      ). Genetic deletion of IRE1α in the mouse brain accelerates the age-dependent decline in cognitive and motor functions, whereas the artificial enforcement of XBP1s expression improves hippocampal function during aging (
      • Cabral-Miranda F.
      • Tamburini G.
      • Martinez G.
      • Medinas M.
      • Gerakis Y.
      • Miedema T.
      • Duran-Aniotz C.
      • Ardiles O.A.
      • Gonzalez C.
      • Sabusap C.
      • BermedoGarcia F.
      • Adamson S.
      • Vitangcol K.
      • Huerta H.
      • Zhang X.
      • Nakamura T.
      • Sardi S.P.
      • Lipton S.A.
      • Kenedy B.K.
      • Hetz C.
      Control of mammalian brain aging by the unfolded protein response (UPR).
      ). Screenings to identify novel IRE1-binding partners identified the actin cytoskeleton regulator filamin A as a major hit (
      • Urra H.
      • Henriquez D.R.
      • Cánovas J.
      • Villarroel-Campos D.
      • Carreras-Sureda A.
      • Pulgar E.
      • Molina E.
      • Hazari Y.M.
      • Limia C.M.
      • Alvarez-Rojas S.
      • et al.
      IRE1α governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A.
      ). Targeting IRE1 in the developing brain resulted in a phenotype resembling periventricular heteropatia, a disease linked to filamin A mutations associated with altered neuronal migration during brain cortex development (
      • Urra H.
      • Henriquez D.R.
      • Cánovas J.
      • Villarroel-Campos D.
      • Carreras-Sureda A.
      • Pulgar E.
      • Molina E.
      • Hazari Y.M.
      • Limia C.M.
      • Alvarez-Rojas S.
      • et al.
      IRE1α governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A.
      ).
      The activity and function of HSF1 under normal brain physiology have been poorly studied in mammals. Analysis of HSF1-deficient mice revealed abnormal neuronal morphology and altered neurogenesis at the dentate gyrus (
      • Uchida S.
      • Hara K.
      • Kobayashi A.
      • Fujimoto M.
      • Otsuki K.
      • Yamagata H.
      • Hobara T.
      • Abe N.
      • Higuchi F.
      • Shibata T.
      • et al.
      Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1.
      ). These effects correlated with depression-like behavioral features, including reduced sociability and anxiety (
      • Uchida S.
      • Hara K.
      • Kobayashi A.
      • Fujimoto M.
      • Otsuki K.
      • Yamagata H.
      • Hobara T.
      • Abe N.
      • Higuchi F.
      • Shibata T.
      • et al.
      Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1.
      ). Interestingly, exposure to maternal stress resulted in strong activation of HSF1 in the developing brain cortex of mouse embryos, and exposure of HSF1-deficient animals to prenatal stress led to structural abnormalities of this brain region, resulting in a higher incidence of seizures after birth (
      • Hashimoto-Torii K.
      • Torii M.
      • Fujimoto M.
      • Nakai A.
      • El Fatimy R.
      • Mezger V.
      • Ju M.J.
      • Ishii S.
      • Chao S.H.
      • Brennand K.J.
      • et al.
      Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders.
      ). HSF1 deficiency also alters motor function and coordination, possibly due to impaired Purkinje cell function in the cerebellum (
      • Ingenwerth M.
      • Estrada V.
      • Stahr A.
      • Müller H.W.
      • von Gall C.
      HSF1-deficiency affects gait coordination and cerebellar calbindin levels.
      ). Physiological stimuli that induce LTP also engage HSF1, contributing to learning and memory-related processes and behavior (
      • Hooper P.L.
      • Durham H.D.
      • Török Z.
      • Hooper P.L.
      • Crul T.
      • Vígh L.
      The central role of heat shock factor 1 in synaptic fidelity and memory consolidation.
      ). All of these studies suggest that the signaling mechanisms that adjust the proteostasis capacity are coupled to central physiological functions of the developing and adult brain.

      Autophagy in brain development and cognition

      The activity of TFEB as an adjustor of lysosomal function has been poorly studied in physiological settings. Recently, the generation of TFEB conditional knockout mice allowed its study in the context of neural stem cell proliferation in the dentate gyrus (
      • Kobayashi T.
      • Piao W.
      • Takamura T.
      • Kori H.
      • Miyachi H.
      • Kitano S.
      • Iwamoto Y.
      • Yamada M.
      • Imayoshi I.
      • Shioda S.
      • et al.
      Enhanced lysosomal degradation maintains the quiescent state of neural stem cells.
      ). Mutations in essential autophagy genes and modulatory factors have been identified in patients with neurodevelopmental diseases affecting the brain, including microcephaly, macrocephaly, autism spectrum disorders (ASDs), and attention deficits, in addition to motor diseases (
      • Fleming A.
      • Rubinsztein D.C.
      Autophagy in Neuronal Development and Plasticity.
      ). Broad genetic ablation of the essential autophagy genes Atg5 and Atg7 in the nervous system results in spontaneous degeneration associated with motor impairment, neuronal loss, and early death (
      • Hara T.
      • Nakamura K.
      • Matsui M.
      • Yamamoto A.
      • Nakahara Y.
      • Suzuki-Migishima R.
      • Yokoyama M.
      • Mishima K.
      • Saito I.
      • Okano H.
      • Mizushima N.
      Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice.
      ;
      • Komatsu M.
      • Waguri S.
      • Chiba T.
      • Murata S.
      • Iwata J.
      • Tanida I.
      • Ueno T.
      • Koike M.
      • Uchiyama Y.
      • Kominami E.
      • Tanaka K.
      Loss of autophagy in the central nervous system causes neurodegeneration in mice.
      ), possibly due to the accumulation of p62 and ubiquitinated insoluble proteins (
      • Komatsu M.
      • Waguri S.
      • Koike M.
      • Sou Y.S.
      • Ueno T.
      • Hara T.
      • Mizushima N.
      • Iwata J.
      • Ezaki J.
      • Murata S.
      • et al.
      Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice.
      ). Interestingly, the embryonic lethality of ATG5 null mice can be rescued by reconstituting ATG5 expression in the nervous system, suggesting essential roles of the pathway during brain development (
      • Komatsu M.
      • Waguri S.
      • Chiba T.
      • Murata S.
      • Iwata J.
      • Tanida I.
      • Ueno T.
      • Koike M.
      • Uchiyama Y.
      • Kominami E.
      • Tanaka K.
      Loss of autophagy in the central nervous system causes neurodegeneration in mice.
      ). Cell culture studies and mouse behavioral work have suggested that the activity of the autophagy pathway regulates adult neuronal stem cells and impacts axonal growth, synaptic assembly, and dendritogenesis (reviewed in
      • Fleming A.
      • Rubinsztein D.C.
      Autophagy in Neuronal Development and Plasticity.
      ). Strategies that modify the expression of ATGs alter synaptic plasticity and learning and memory and are associated with morphological alterations (
      • Glatigny M.
      • Moriceau S.
      • Rivagorda M.
      • Ramos-Brossier M.
      • Nascimbeni A.C.
      • Lante F.
      • Shanley M.R.
      • Boudarene N.
      • Rousseaud A.
      • Friedman A.K.
      • et al.
      Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline.
      ;
      • Hernandez D.
      • Torres C.A.
      • Setlik W.
      • Cebrián C.
      • Mosharov E.V.
      • Tang G.
      • Cheng H.C.
      • Kholodilov N.
      • Yarygina O.
      • Burke R.E.
      • et al.
      Regulation of presynaptic neurotransmission by macroautophagy.
      ;
      • Yan J.
      • Porch M.W.
      • Court-Vazquez B.
      • Bennett M.V.L.
      • Zukin R.S.
      Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice.
      ). Remarkably, enhancement of autophagy in the hippocampus resulted in reduced cognitive decline during aging (
      • Glatigny M.
      • Moriceau S.
      • Rivagorda M.
      • Ramos-Brossier M.
      • Nascimbeni A.C.
      • Lante F.
      • Shanley M.R.
      • Boudarene N.
      • Rousseaud A.
      • Friedman A.K.
      • et al.
      Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline.
      ). Selective disruption of Atg5 expression in astrocytes also affects synaptic functions and triggers cognitive deficits (
      • Kim H.J.
      • Cho M.H.
      • Shim W.H.
      • Kim J.K.
      • Jeon E.Y.
      • Kim D.H.
      • Yoon S.Y.
      Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects.
      ), whereas targeting its function in oligodendrocytes reduces their survival (
      • Bankston A.N.
      • Forston M.D.
      • Howard R.M.
      • Andres K.R.
      • Smith A.E.
      • Ohri S.S.
      • Bates M.L.
      • Bunge M.B.
      • Whittemore S.R.
      Autophagy is essential for oligodendrocyte differentiation, survival, and proper myelination.
      ). Mechanistically, ATG7 has been shown to regulate synaptosome degradation, impacting the expression of synaptic proteins, dendritic spine density, and neuronal connectivity (
      • Kim H.J.
      • Cho M.H.
      • Shim W.H.
      • Kim J.K.
      • Jeon E.Y.
      • Kim D.H.
      • Yoon S.Y.
      Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects.
      ). ATG5 deficiency in microglia increases brain inflammation and reduces levels of BDNF, resulting in depression-like behavioral phenotypes (
      • Tan X.
      • Du X.
      • Jiang Y.
      • Botchway B.O.A.
      • Hu Z.
      • Fang M.
      Inhibition of Autophagy in Microglia Alters Depressive-Like Behavior via BDNF Pathway in Postpartum Depression.
      ). Interestingly, synaptic proteins may also regulate central autophagy components through protein-protein interactions (
      • Okerlund N.D.
      • Schneider K.
      • Leal-Ortiz S.
      • Montenegro-Venegas C.
      • Kim S.A.
      • Garner L.C.
      • Waites C.L.
      • Gundelfinger E.D.
      • Reimer R.J.
      • Garner C.C.
      Bassoon Controls Presynaptic Autophagy through Atg5.
      ). At the behavioral level, different reports have suggested that the genetic targeting of autophagy components in mouse results in learning and memory deficits, anxiety-like behaviors, and other cognitive dysfunctions (
      • Fleming A.
      • Rubinsztein D.C.
      Autophagy in Neuronal Development and Plasticity.
      ). In contrast to all these studies, no reports are available linking CMA or microautophagy to normal brain physiology in vivo.

      Adjustment of global proteostasis by neuronal stress pathways

      The use of simple model organisms such as C. elegans has been instrumental to define and uncover new frontiers in the field. Although this review focuses mostly on evidence provided using mammalian model systems in vivo, this section highlights emerging concepts discovered in nematodes that are central to understanding the interconnection between stress pathways in the brain and homeostatic regulation of other tissues.
      The control of proteostasis at distance was first identified in the HSR field, where cell-autonomous activation of HSF1 in neurons triggers a mirror reaction in other tissues that provides protection against tissue damage and aging (
      • Prahlad V.
      • Cornelius T.
      • Morimoto R.I.
      Regulation of the cellular heat shock response in Caenorhabditis elegans by thermosensory neurons.
      ; reviewed in
      • Morimoto R.I.
      Cell-Nonautonomous Regulation of Proteostasis in Aging and Disease.
      ). Optogenetic activation of temperature-sensitive neurons engages the HSR in non-neuronal tissue in the absence of stress (
      • Tatum M.C.
      • Ooi F.K.
      • Chikka M.R.
      • Chauve L.
      • Martinez-Velazquez L.A.
      • Steinbusch H.W.M.
      • Morimoto R.I.
      • Prahlad V.
      Neuronal serotonin release triggers the heat shock response in C. elegans in the absence of temperature increase.
      ), suggesting that neurons are able to orchestrate the establishment of “alert” responses in peripheral organs to protect organisms from eventual damage. During aging, worms are resistant to a variety of proteostasis stressors, such as heat shock and ER stress. Restoration of the buffering capacity of the ER proteostasis network through the overexpression of the active XBP1s form in neurons significantly prolongs lifespan and involves activation of the pathway in the gut (
      • Taylor R.C.
      • Dillin A.
      XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity.
      ; Figure 3). Communication between neurons and the intestine depends upon the release of neuronal factors, improving lysosome activity and lipid metabolism (reviewed in
      • Taylor R.C.
      • Hetz C.
      Mastering organismal aging through the endoplasmic reticulum proteostasis network.
      ). Similarly, a recent study suggested that glial cells also regulate cell-non-autonomous UPR activation in the gut to extend lifespan in C. elegans (
      • Frakes A.E.
      • Metcalf M.G.
      • Tronnes S.U.
      • Bar-Ziv R.
      • Durieux J.
      • Gildea H.K.
      • Kandahari N.
      • Monshietehadi S.
      • Dillin A.
      Four glial cells regulate ER stress resistance and longevity via neuropeptide signaling in C. elegans.
      ).
      Figure thumbnail gr3
      Figure 3Cell-non-autonomous control of the UPR
      Left: apart from its cell-autonomous effect on leptin/insulin signaling, XBP1s activation in POMC neurons propagates to the liver via a non-cell-autonomous mechanism, where XBP1s activates canonical UPR target genes and metabolic enzymes in hepatocytes. These events may contribute to reduced hepatic glucose and the control of global energy metabolism. Food perception engages the hypothalamus to propagate signals that activate XBP1 mRNA splicing in the liver to control metabolism. Right: in C. elegans, expression of XBP1s in neurons signals to distal tissues (i.e., the intestine) to activate IRE1/XBP1 in a non-cell-autonomous manner, driving proteostatic changes that are central to lifespan extension, including ER stress resistance, lipid metabolism, and lysosomal/autophagy function. An unknown secreted ER stress signal (SERSS) may mediate the communication between neurons and the gut to engage the UPR. In addition, expression of XBP1s in cephalic glia of C. elegans also increases lifespan independently of neurons, engaging the same UPR signaling branch in the gut. This process depends on neuropeptide release.
      Global control of organismal proteostasis by neuronal stress pathways has been suggested in mammals based on very limited studies. Expression of XBP1s in pro-opiomelanocortin (POMC) neurons of the hypothalamus has a wide impact on the control of whole-body metabolism and is associated with cell-non-autonomous activation of the UPR in the liver (
      • Williams K.W.
      • Liu T.
      • Kong X.
      • Fukuda M.
      • Deng Y.
      • Berglund E.D.
      • Deng Z.
      • Gao Y.
      • Liu T.
      • Sohn J.W.
      • et al.
      Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis.
      ; Figure 3). Of note, the activity of proteostasis stress pathways in the hypothalamus has been linked to the control of energy metabolism and obesity (see examples in
      • Ingenwerth M.
      • Noichl E.
      • Stahr A.
      • Korf H.W.
      • Reinke H.
      • von Gall C.
      Heat Shock Factor 1 Deficiency Affects Systemic Body Temperature Regulation.
      ;
      • Park S.
      • Aintablian A.
      • Coupe B.
      • Bouret S.G.
      The endoplasmic reticulum stress-autophagy pathway controls hypothalamic development and energy balance regulation in leptin-deficient neonates.
      ;
      • Xiao Y.
      • Deng Y.
      • Yuan F.
      • Xia T.
      • Liu H.
      • Li Z.
      • Chen S.
      • Liu Z.
      • Ying H.
      • Liu Y.
      • et al.
      An ATF4-ATG5 signaling in hypothalamic POMC neurons regulates obesity.
      ). Interestingly, the perception of food was shown to induce global metabolic changes involving systemic UPR activation (
      • Brandt C.
      • Nolte H.
      • Henschke S.
      • Engström Ruud L.
      • Awazawa M.
      • Morgan D.A.
      • Gabel P.
      • Sprenger H.G.
      • Hess M.E.
      • Günther S.
      • et al.
      Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation.
      ). Food perception or the optogenetic activation of POMC neurons was sufficient to promote hepatic XBP1 mRNA splicing as an effecter response (
      • Brandt C.
      • Nolte H.
      • Henschke S.
      • Engström Ruud L.
      • Awazawa M.
      • Morgan D.A.
      • Gabel P.
      • Sprenger H.G.
      • Hess M.E.
      • Günther S.
      • et al.
      Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation.
      ). However, whether this inter-organ pathway regulates lifespan remains an open question. Overall, these studies suggest a new concept where stress sensors in the brain communicate and coordinate proteostasis in other organs to adjust metabolic activities.

      Proteostasis impairment in neurodegenerative diseases

      The deposit of protein aggregates in the brain on fibrillar structures is a well-accepted feature of age-related neurodegenerative diseases. Since proteostasis impairment has been suggested as a hallmark of aging, it is proposed that a vicious cycle may exist that facilitates the accumulation of abnormal misfolded species, which further alter proteostasis to enhance protein aggregation (
      • Kaushik S.
      • Cuervo A.M.
      Proteostasis and aging.
      ). As a central protective mechanism, the ability to engage signaling pathways to boost the proteostasis capacity of a cell sets the threshold for disease manifestation by maintaining abnormal protein aggregation to a level that is compatible with brain function, an equilibrium that is lost as we age. This is evidenced by the fact that genetic forms of degenerative diseases manifest only late in life despite the fact that mutant proteins are expressed during youth.
      Why are disease-related proteins toxic? There is no simple answer to this question. Small oligomers have common properties independent of the specific sequence of the proteins involved that favor abnormal interactions with many cellular components, including membranes and proteins. Different screenings are now available suggesting that one of the main nodes of the proteostasis network affected in neurodegenerative diseases involves different components of the secretory pathway, resulting in chronic ER stress (
      • Hetz C.
      • Saxena S.
      ER stress and the unfolded protein response in neurodegeneration.
      ). The accumulation of dipeptide repeats due to C9orf72 mutations underlies the etiology of the vast majority of familial ALS and frontotemporal dementia (FTD) cases. A whole-genome CRISPR screening to identify modifiers of C9orf72 pathogenesis revealed a cluster of secretory pathway genes as a major hit (
      • Kramer N.J.
      • Haney M.S.
      • Morgens D.W.
      • Jovičić A.
      • Couthouis J.
      • Li A.
      • Ousey J.
      • Ma R.
      • Bieri G.
      • Tsui C.K.
      • et al.
      CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.
      ). Similarly, ER stress is among the main gene expression signatures identified in brain tissue of C9orf72-ALS cases (
      • Prudencio M.
      • Belzil V.V.
      • Batra R.
      • Ross C.A.
      • Gendron T.F.
      • Pregent L.J.
      • Murray M.E.
      • Overstreet K.K.
      • Piazza-Johnston A.E.
      • Desaro P.
      • et al.
      Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS.
      ) and mutant SOD1 mice, a gold standard in ALS research (
      • Sun S.
      • Sun Y.
      • Ling S.C.
      • Ferraiuolo L.
      • McAlonis-Downes M.
      • Zou Y.
      • Drenner K.
      • Wang Y.
      • Ditsworth D.
      • Tokunaga S.
      • et al.
      Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS.
      ), consistent with previous studies that profiled the gene expression pattern of vulnerable and resistant motoneurons in the model (
      • Filézac de L’Etang A.
      • Maharjan N.
      • Cordeiro Braña M.
      • Ruegsegger C.
      • Rehmann R.
      • Goswami A.
      • Roos A.
      • Troost D.
      • Schneider B.L.
      • Weis J.
      • Saxena S.
      Marinesco-Sjögren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS.
      ;
      • Saxena S.
      • Cabuy E.
      • Caroni P.
      A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice.
      ). In Parkinson, yeast screenings to identify mediators of alpha-synuclein toxicity also revealed that components of the secretory pathway are major targets (
      • Cooper A.A.
      • Gitler A.D.
      • Cashikar A.
      • Haynes C.M.
      • Hill K.J.
      • Bhullar B.
      • Liu K.
      • Xu K.
      • Strathearn K.E.
      • Liu F.
      • et al.
      Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models.
      ). Alpha-synuclein abnormally interacts with Rab1, affecting the trafficking of proteins between the ER and the Golgi apparatus, altering protein maturation. Similarly, unbiased studies using human neurons derived from induced pluripotent stem cells (iPSCs) of Parkinson’s disease (PD), ALS, and FTD patients suggested the occurrence of abnormal levels of ER stress in the model (
      • Chung C.Y.
      • Khurana V.
      • Auluck P.K.
      • Tardiff D.F.
      • Mazzulli J.R.
      • Soldner F.
      • Baru V.
      • Lou Y.
      • Freyzon Y.
      • Cho S.
      • et al.
      Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons.
      ;
      • Hetz C.
      • Saxena S.
      ER stress and the unfolded protein response in neurodegeneration.
      ). Interactome screenings for mutant Huntingtin also uncovered ERAD components as main binding partners, suggesting that the disposal of naturally occurring misfolded cargoes from the ER to the cytosol is impaired in Huntington’s disease (HD) neurons (
      • Duennwald M.L.
      • Lindquist S.
      Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity.
      ). Many other studies indicate that abnormal protein-protein interactions driven by disease-related proteins can alter the function of the secretory pathway and the UPR (
      • Hetz C.
      • Saxena S.
      ER stress and the unfolded protein response in neurodegeneration.
      ). Similar findings were reported for components of the autophagy machinery. This results in autophagy and CMA impairment and the abnormal accumulation of cargo proteins and damaged organelles, as reported in ALS, Alzheimer’s disease (AD), HD, and PD (
      • Scrivo A.
      • Bourdenx M.
      • Pampliega O.
      • Cuervo A.M.
      Selective autophagy as a potential therapeutic target for neurodegenerative disorders.
      ). Examples of a direct disruption of the HSR by disease-related proteins are also available (
      • Gomez-Pastor R.
      • Burchfiel E.T.
      • Neef D.W.
      • Jaeger A.M.
      • Cabiscol E.
      • McKinstry S.U.
      • Doss A.
      • Aballay A.
      • Lo D.C.
      • Akimov S.S.
      • et al.
      Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s disease.
      ), in addition to perturbations to the functions of chaperones due to mutations, sequestration by aggregates, or oxidative modifications (
      • Hipp M.S.
      • Kasturi P.
      • Hartl F.U.
      The proteostasis network and its decline in ageing.
      ). In the long-term, these phenomena may unbalance the neuronal proteome, leading to synaptic dysfunction and alterations to other essential neuronal processes, followed by synaptic loss and neurodegeneration (Figure 4). In the next subsections, an overview of the studies linking adaptive signaling pathways to protein-folding stress in neurodegenerative diseases is discussed.
      Figure thumbnail gr4
      Figure 4Contribution of proteostasis unbalance to brain diseases
      Disease-related misfolded proteins can reduce the synthesis of synaptic proteins due to chronic activation of the ISR. Similarly, alterations to the chaperone-folding machinery, autophagy impairment, or disruption of adaptive stress pathways (the UPR and HSR) could result in neuronal proteome unbalance. All of these defects adversely influence various processes that are essential for sustaining brain function, including connectivity and synaptic plasticity, neurogenesis, and oligodendrocyte survival. In addition, protein-folding stress may enhance the spreading of pathological misfolded proteins through the brain or exacerbate damaging proinflammatory reactions mediated by astrocytes. Together, these events may influence braid development, trigger neurodegeneration, and result in cognitive and motor impairments. Examples of possible intervention strategies to improve neuronal proteostasis using gene therapy or pharmacology are indicated.

      The UPR and the ISR in synaptic dysfunction and neurodegeneration

      Loss-of-function mutations in EIF2AK3, which encodes PERK, results in Wolcott-Rallison syndrome, a rare disease with early signs of neurodegeneration, cognitive decline, and diabetes mellitus. In addition, partial loss-of-function mutations in eIF2B cause a neurodegenerative disorder called vanishing white matter disease, involving childhood onset of neurological deterioration dominated by cerebellar ataxia and axonal damage. The development of pharmacological PERK inhibitors uncovered a new angle in the field where the sustained activation of PERK due to chronic stress contributes to early disease stages by blocking the translation of key synaptic proteins (
      • Moreno J.A.
      • Radford H.
      • Peretti D.
      • Steinert J.R.
      • Verity N.
      • Martin M.G.
      • Halliday M.
      • Morgan J.
      • Dinsdale D.
      • Ortori C.A.
      • et al.
      Sustained translational repression by eIF2α-P mediates prion neurodegeneration.
      ). This unbalance in the neuronal proteome results in cognitive impairment and late neurodegeneration, as demonstrated in prion-related disorders, FTD, and PD models (
      • Mercado G.
      • Castillo V.
      • Soto P.
      • López N.
      • Axten J.M.
      • Sardi S.P.
      • Hoozemans J.J.M.
      • Hetz C.
      Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of Parkinson’s disease.
      ;
      • Moreno J.A.
      • Halliday M.
      • Molloy C.
      • Radford H.
      • Verity N.
      • Axten J.M.
      • Ortori C.A.
      • Willis A.E.
      • Fischer P.M.
      • Barrett D.A.
      • Mallucci G.R.
      Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice.
      ;
      • Radford H.
      • Moreno J.A.
      • Verity N.
      • Halliday M.
      • Mallucci G.R.
      PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia.
      ). Importantly, these studies proposed that a temporal window may exist to recover functional impairments before neuronal loss has occurred. Since PERK inhibitors have adverse effects on pancreatic function, other approaches have been developed to inhibit PERK or ISR signaling. The use of ISRIB has proven that a partial block in protein translational is sufficient to improve neuronal function in various neurodegenerative diseases (
      • Bugallo R.
      • Marlin E.
      • Baltanás A.
      • Toledo E.
      • Ferrero R.
      • Vinueza-Gavilanes R.
      • Larrea L.
      • Arrasate M.
      • Aragón T.
      Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis.
      ;
      • Halliday M.
      • Radford H.
      • Sekine Y.
      • Moreno J.
      • Verity N.
      • le Quesne J.
      • Ortori C.A.
      • Barrett D.A.
      • Fromont C.
      • Fischer P.M.
      • et al.
      Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity.
      ). Molecular studies have indicated that ISRIB is effective in inhibiting the ISR only under conditions of partial eIF2α phosphorylation (
      • Rabouw H.H.
      • Langereis M.A.
      • Anand A.A.
      • Visser L.J.
      • de Groot R.J.
      • Walter P.
      • van Kuppeveld F.J.M.
      Small molecule ISRIB suppresses the integrated stress response within a defined window of activation.
      ). Other small molecules that mimic the activity of ISRIB, such as the US Food and Drug Administration (FDA)-approved compound trazadone, are effective in providing broad neuroprotection (
      • Halliday M.
      • Radford H.
      • Zents K.A.M.
      • Molloy C.
      • Moreno J.A.
      • Verity N.C.
      • Smith E.
      • Ortori C.A.
      • Barrett D.A.
      • Bushell M.
      • Mallucci G.R.
      Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice.
      ). Importantly, in addition to PERK, GCN2 and PKR contribute to neurodegeneration in AD, linking proteostasis unbalance to neuroinflammation and metabolic dysfunction (
      • Gerakis Y.
      • Hetz C.
      Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer’s disease.
      ). Administration of ISRIB to AD mice improves synaptic plasticity and memory-associated behaviors, associated with a rescue of protein synthesis in the hippocampus (
      • Oliveira M.M.
      • Lourenco M.V.
      • Longo F.
      • Kasica N.P.
      • Yang W.
      • Ureta G.
      • Ferreira D.D.P.
      • Mendonça P.H.J.
      • Bernales S.
      • Ma T.
      • et al.
      Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease.
      ). The idea that extending eIF2α phosphorylation over time is also protective has been tested using a series of compounds that inhibit the inducible and constitutive eIF2α phosphatases. These compounds have proven efficacy in models of ALS, HD, and Charcot-Marie Tooth 1B disease (
      • Das I.
      • Krzyzosiak A.
      • Schneider K.
      • Wrabetz L.
      • D’Antonio M.
      • Barry N.
      • Sigurdardottir A.
      • Bertolotti A.
      Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit.
      ;
      • Krzyzosiak A.
      • Sigurdardottir A.
      • Luh L.
      • Carrara M.
      • Das I.
      • Schneider K.
      • Bertolotti A.
      Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B.
      ). Since the ISR regulates not only protein translation, but also reprograms gene expression through the concerted action of ATF4/CHOP/ATF5, more studies are needed to define the exact contribution of the pathway to neurodegenerative diseases.
      Canonical components of the UPR have been also exploited to modify the course of neurodegenerative diseases. Artificial enforcement of XBP1s-depedent gene expression programs using gene therapy has revealed important neuroprotective effects in various disease settings. Overexpression of XBP1s in the brain using gene therapy alleviates disease features in models of HD, spinal cord injury, peripheral nerve degeneration, glaucoma, and PD (
      • Valenzuela V.
      • Jackson K.L.
      • Sardi S.P.
      • Hetz C.
      Gene Therapy Strategies to Restore ER Proteostasis in Disease.
      ). However, studies using XBP1 conditional knockout animals depict a complex scenario in the nervous system. Despite the well-demonstrated role of PERK signaling in prion disease, ablation of XBP1 expression has negligible effects on disease progression (
      • Hetz C.
      • Lee A.H.
      • Gonzalez-Romero D.
      • Thielen P.
      • Castilla J.
      • Soto C.
      • Glimcher L.H.
      Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis.
      ). In ALS, PD, and HD models, genetic ablation of XBP1 during brain development provides protection and involves a shift in the proteostasis network that increases autophagy levels (
      • Hetz C.
      • Thielen P.
      • Matus S.
      • Nassif M.
      • Court F.
      • Kiffin R.
      • Martinez G.
      • Cuervo A.M.
      • Brown R.H.
      • Glimcher L.H.
      XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy.
      ;
      • Valdés P.
      • Mercado G.
      • Vidal R.L.
      • Molina C.
      • Parsons G.
      • Court F.A.
      • Martinez A.
      • Galleguillos D.
      • Armentano D.
      • Schneider B.L.
      • Hetz C.
      Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1.
      ;
      • Vidal R.L.
      • Figueroa A.
      • Court F.A.
      • Thielen P.
      • Molina C.
      • Wirth C.
      • Caballero B.
      • Kiffin R.
      • Segura-Aguilar J.
      • Cuervo A.M.
      • et al.
      Targeting the UPR transcription factor XBP1 protects against Huntington’s disease through the regulation of FoxO1 and autophagy.
      ). The protective effects of XBP1 deficiency were also mapped to the upregulation of IGF2, triggering a signaling cascade that reduces the intracellular load of protein aggregates through their extracellular disposal (
      • García-Huerta P.
      • Troncoso-Escudero P.
      • Wu D.
      • Thiruvalluvan A.
      • Cisternas-Olmedo M.
      • Henríquez D.R.
      • Plate L.
      • Chana-Cuevas P.
      • Saquel C.
      • Thielen P.
      • et al.
      Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates.
      ).
      ATF6f and XBP1s are known to physically interact, forming an active heterodimer that drives specific gene expression programs toward stress mitigation. A recent study demonstrated that the artificial enforcement of ATF6f-XBP1s heterodimers using gene therapy has a superior capacity to alleviate neurodegeneration in HD and PD models when compared with the expression of the single transcription factors (
      • Vidal R.L.
      • Sepulveda D.
      • Troncoso-Escudero P.
      • Garcia-Huerta P.
      • Gonzalez C.
      • Plate L.
      • Jerez C.
      • Canovas J.
      • Rivera C.A.
      • Castillo V.
      • et al.
      Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration.
      ). Mutations in ATF6 are associated with retinal malformations and congenital vision loss in humans (
      • Kohl S.
      • Zobor D.
      • Chiang W.C.
      • Weisschuh N.
      • Staller J.
      • Gonzalez Menendez I.
      • Chang S.
      • Beck S.C.
      • Garcia Garrido M.
      • Sothilingam V.
      • et al.
      Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.
      ). Small molecules to activate ATF6 are effective in protecting the brain against ischemia-reperfusion (
      • Blackwood E.A.
      • Azizi K.
      • Thuerauf D.J.
      • Paxman R.J.
      • Plate L.
      • Kelly J.W.
      • Wiseman R.L.
      • Glembotski C.C.
      Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis.
      ). In contrast, strategies to overexpress ATF4 in the brain resulted in neuronal loss (
      • Gully J.C.
      • Sergeyev V.G.
      • Bhootada Y.
      • Mendez-Gomez H.
      • Meyers C.A.
      • Zolotukhin S.
      • Gorbatyuk M.S.
      • Gorbatyuk O.S.
      Up-regulation of activating transcription factor 4 induces severe loss of dopamine nigral neurons in a rat model of Parkinson’s disease.
      ). The dual role of ATF4 in cell survival and death is reflected in the fact that the use of genetic PERK ablation, ISRIB, or eIF2α phosphatase inhibitors in models of neurodegeneration has provided disparate results that are still difficult to consolidate, possibly due to differences in the experimental conditions used (
      • Costa-Mattioli M.
      • Walter P.
      The integrated stress response: From mechanism to disease.
      ;
      • Hetz C.
      • Axten J.M.
      • Patterson J.B.
      Pharmacological targeting of the unfolded protein response for disease intervention.
      ).

      Enforcement of HSF1 to alleviate neurodegeneration

      Strategies to activate or overexpress HSF1 in the brain also protect against neurodegeneration in vivo. Overexpression of HSF1 in an AD model reduced the load of amyloid-β plaques and ameliorated cognitive defects (
      • Pierce A.
      • Podlutskaya N.
      • Halloran J.J.
      • Hussong S.A.
      • Lin P.Y.
      • Burbank R.
      • Hart M.J.
      • Galvan V.
      Over-expression of heat shock factor 1 phenocopies the effect of chronic inhibition of TOR by rapamycin and is sufficient to ameliorate Alzheimer’s-like deficits in mice modeling the disease.
      ). In agreement with this, small molecules that inhibit HSP90 trigger HSF1 translocation to the nucleus, correlating with improved synaptic function in models of FTD (
      • Wang B.
      • Liu Y.
      • Huang L.
      • Chen J.
      • Li J.J.
      • Wang R.
      • Kim E.
      • Chen Y.
      • Justicia C.
      • Sakata K.
      • et al.
      A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer’s mouse model via an HSF1-mediated mechanism.
      ). Similarly, enhancement of HSF1 activity using the Hsp90 inhibitor 17-AAG increased the levels of synaptic proteins such as synapsin I, synaptophysin, and PSD95 in neurons in an AD model (
      • Chen Y.
      • Wang B.
      • Liu D.
      • Li J.J.
      • Xue Y.
      • Sakata K.
      • Zhu L.Q.
      • Heldt S.A.
      • Xu H.
      • Liao F.F.
      Hsp90 chaperone inhibitor 17-AAG attenuates Aβ-induced synaptic toxicity and memory impairment.
      ). HSF1 deficiency also exacerbates Tau-mediated pathology correlating with the occurrence of chronic ER stress, suggesting a delicate balance between both pathways (
      • Kim E.
      • Sakata K.
      • Liao F.F.
      Bidirectional interplay of HSF1 degradation and UPR activation promotes tau hyperphosphorylation.
      ).
      Impairment of HSF1 function due to its proteasomal degradation has been reported in models of HD (
      • Gomez-Pastor R.
      • Burchfiel E.T.
      • Neef D.W.
      • Jaeger A.M.
      • Cabiscol E.
      • McKinstry S.U.
      • Doss A.
      • Aballay A.
      • Lo D.C.
      • Akimov S.S.
      • et al.
      Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s disease.
      ), a phenomenon that may exacerbate polyglutamine aggregation and toxicity (
      • Kondo N.
      • Katsuno M.
      • Adachi H.
      • Minamiyama M.
      • Doi H.
      • Matsumoto S.
      • Miyazaki Y.
      • Iida M.
      • Tohnai G.
      • Nakatsuji H.
      • et al.
      Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration.
      ). Genetic restoration of this defect by the lentiviral-mediated delivery of HSF1 into the brain (
      • Kondo N.
      • Katsuno M.
      • Adachi H.
      • Minamiyama M.
      • Doi H.
      • Matsumoto S.
      • Miyazaki Y.
      • Iida M.
      • Tohnai G.
      • Nakatsuji H.
      • et al.
      Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration.
      ) or the use of transgenic mice that overexpress an active form of HSF1 delays experimental HD (
      • Fujimoto M.
      • Takaki E.
      • Hayashi T.
      • Kitaura Y.
      • Tanaka Y.
      • Inouye S.
      • Nakai A.
      Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models.
      ). These examples indicate that strategies that enhance the adaptive capacity of the proteostasis network in the cytosol through HSF1 also improve brain function and reduce abnormal protein aggregation in the context of neurodegeneration.

      Autophagy enhancement in neurodegenerative diseases

      The lysosomal/autophagy pathway has been extensively studied as a strategy to enhance the degradation of abnormal protein aggregates. Many small molecules are available that can enhance autophagy activity with a therapeutic gain, highlighting various drugs that also extend lifespan in model organisms (reviewed in
      • Boland B.
      • Yu W.H.
      • Corti O.
      • Mollereau B.
      • Henriques A.
      • Bezard E.
      • Pastores G.M.
      • Rubinsztein D.C.
      • Nixon R.A.
      • Duchen M.R.
      • et al.
      Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.
      ). Since several small molecules that enhance autophagy and protect against neurodegeneration have many additional targets and cellular effects, here, I discuss examples of enhancement of autophagy using direct genetic approaches. Gene therapy to express TFEB or Beclin-1 in the brain is beneficial in models of neurodegeneration such as PD and AD (see examples in
      • Bajaj L.
      • Lotfi P.
      • Pal R.
      • Ronza A.D.
      • Sharma J.
      • Sardiello M.
      Lysosome biogenesis in health and disease.
      ;
      • Decressac M.
      • Mattsson B.
      • Weikop P.
      • Lundblad M.
      • Jakobsson J.
      • Björklund A.
      TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity.
      ;
      • Pickford F.
      • Masliah E.
      • Britschgi M.
      • Lucin K.
      • Narasimhan R.
      • Jaeger P.A.
      • Small S.
      • Spencer B.
      • Rockenstein E.
      • Levine B.
      • Wyss-Coray T.
      The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice.
      ;
      • Polito V.A.
      • Li H.
      • Martini-Stoica H.
      • Wang B.
      • Yang L.
      • Xu Y.
      • Swartzlander D.B.
      • Palmieri M.
      • di Ronza A.
      • Lee V.M.
      • et al.
      Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB.
      ;
      • Torra A.
      • Parent A.
      • Cuadros T.
      • Rodríguez-Galván B.
      • Ruiz-Bronchal E.
      • Ballabio A.
      • Bortolozzi A.
      • Vila M.
      • Bové J.
      Overexpression of TFEB Drives a Pleiotropic Neurotrophic Effect and Prevents Parkinson’s Disease-Related Neurodegeneration.
      ;
      • Xiao Q.
      • Yan P.
      • Ma X.
      • Liu H.
      • Perez R.
      • Zhu A.
      • Gonzales E.
      • Tripoli D.L.
      • Czerniewski L.
      • Ballabio A.
      • et al.
      Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing Aβ Generation and Amyloid Plaque Pathogenesis.
      ). CMA is also involved in neurodegenerative disease, because key proteins underlying the etiology of these conditions are substrates of CMA (
      • Kaushik S.
      • Cuervo A.M.
      Proteostasis and aging.
      ). Strategies to enhance CMA, such as LAMP2 activation/overexpression, may provide protection from a variety of age-related neurodegenerative diseases, as demonstrated in PD models (
      • Xilouri M.
      • Brekk O.R.
      • Landeck N.
      • Pitychoutis P.M.
      • Papasilekas T.
      • Papadopoulou-Daifoti Z.
      • Kirik D.
      • Stefanis L.
      Boosting chaperone-mediated autophagy in vivo mitigates α-synuclein-induced neurodegeneration.
      ) and other tissues such as the liver (
      • Kaushik S.
      • Cuervo A.M.
      The coming of age of chaperone-mediated autophagy.
      ).

      Cell-non-autonomous contribution of the proteostasis network to neurodegeneration

      Most neurodegenerative diseases are characterized by abnormal levels of brain inflammation and axonal degeneration associated with the reactive activation of astrocytes and microglia and loss of oligodendrocytes and Schwann cells. Several studies indicate that stress pathways that adjust proteostasis regulate the function of glial cells, contributing to neuronal dysfunction through cell-non-autonomous mechanisms (Figure 4). This phenomenon has been extensively reported in models of multiple sclerosis and mechanical injury to the nervous system. For example, the UPR has essential functions in oligodendrocyte differentiation, proliferation, and survival, a cell type that is highly susceptible to ER stress, possibly because of their intrinsic secretory nature. PERK/eIF2α signaling has been extensively studied in oligodendrocytes and has a beneficial impact in experimental models of multiple sclerosis (
      • Way S.W.
      • Popko B.
      Harnessing the integrated stress response for the treatment of multiple sclerosis.
      ). XBP1 and ATF4 deficiency reduces motor recovery after mechanical injury to the spinal cord (
      • Valenzuela V.
      • Collyer E.
      • Armentano D.
      • Parsons G.B.
      • Court F.A.
      • Hetz C.
      Activation of the unfolded protein response enhances motor recovery after spinal cord injury.
      ), where the activity of XBP1 in oligodendrocytes was shown to be essential for oligodendrocyte survival after damage (
      • Saraswat Ohri S.
      • Howard R.M.
      • Liu Y.
      • Andres K.R.
      • Shepard C.T.
      • Hetman M.
      • Whittemore S.R.
      Oligodendrocyte-specific deletion of Xbp1 exacerbates the endoplasmic reticulum stress response and restricts locomotor recovery after thoracic spinal cord injury.
      ). Interestingly, a recent screening to identify factors driving proinflammatory responses in the CNS uncovered XBP1 as a central regulator of astrocyte activity, controlling the expression of diverse proinflammatory cytokines (
      • Wheeler M.A.
      • Jaronen M.
      • Covacu R.
      • Zandee S.E.J.
      • Scalisi G.
      • Rothhammer V.
      • Tjon E.C.
      • Chao C.C.
      • Kenison J.E.
      • Blain M.
      • et al.
      Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation.
      ). Ablation of XBP1 expression specifically in astrocytes protected against experimental multiple sclerosis (
      • Wheeler M.A.
      • Jaronen M.
      • Covacu R.
      • Zandee S.E.J.
      • Scalisi G.
      • Rothhammer V.
      • Tjon E.C.
      • Chao C.C.
      • Kenison J.E.
      • Blain M.
      • et al.
      Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation.
      ). Besides, the overactivation of PERK in models of neurodegeneration exacerbates the degenerative cascade by altering the astrocyte secretome, impacting neuronal synaptogenesis (
      • Smith H.L.
      • Freeman O.J.
      • Butcher A.J.
      • Holmqvist S.
      • Humoud I.
      • Schätzl T.
      • Hughes D.T.
      • Verity N.C.
      • Swinden D.P.
      • Hayes J.
      • et al.
      Astrocyte Unfolded Protein Response Induces a Specific Reactivity State that Causes Non-Cell-Autonomous Neuronal Degeneration.
      ). The expression of TFEB in astrocytes has been shown to enhance the uptake of Tau oligomers by astrocytes, limiting the spreading of protein aggregates through the brain (
      • Martini-Stoica H.
      • Cole A.L.
      • Swartzlander D.B.
      • Chen F.
      • Wan Y.W.
      • Bajaj L.
      • Bader D.A.
      • Lee V.M.Y.
      • Trojanowski J.Q.
      • Liu Z.
      • et al.
      TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading.
      ). Similarly, strategies to express TFEB in astrocytes increase the clearance of amyloid β in animal models of AD (
      • Xiao Q.
      • Yan P.
      • Ma X.
      • Liu H.
      • Perez R.
      • Zhu A.
      • Gonzales E.
      • Burchett J.M.
      • Schuler D.R.
      • Cirrito J.R.
      • et al.
      Enhancing astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis.
      ). TFEB expression in oligodendrocytes also regulates their myelinating activity (
      • Sun L.O.
      • Mulinyawe S.B.
      • Collins H.Y.
      • Ibrahim A.
      • Li Q.
      • Simon D.J.
      • Tessier-Lavigne M.
      • Barres B.A.
      Spatiotemporal Control of CNS Myelination by Oligodendrocyte Programmed Cell Death through the TFEB-PUMA Axis.
      ). Finally, accumulating studies also indicate that in the context of brain cancer and glioblastoma, stress pathways such as the UPR are essential for tumor growth (
      • Obacz J.
      • Avril T.
      • Le Reste P.J.
      • Urra H.
      • Quillien V.
      • Hetz C.
      • Chevet E.
      Endoplasmic reticulum proteostasis in glioblastoma-From molecular mechanisms to therapeutic perspectives.
      ). All of these studies have added complexity to the field and illustrate the need to develop systematic approaches to address the specific contribution of the signaling pathways that adjust proteostasis to the function of different cell types in the brain.

      Perspective

      The molecular explanation of why the activity of the proteostasis network declines with age is still unclear, but this decline may be the result of a lack of evolutionary pressure to maintain the integrity of the proteome after reproduction. Although the community widely accepts this concept, actual data in human brain tissue and mammalian models is very limiting and the functional significance of proteostasis to normal aging is just starting to emerge. The proposed model is contraintuitive, because it is expected that due to accumulative damage during life (e.g., oxidative stress and increased errors in translation and DNA replication), aged cells should be highly susceptible to proteotoxic stress. In fact, studies characterizing tissues derived from aged rodents or elderly humans indicate a progressive upregulation of diverse chaperones and components of stress pathways such as the UPR (
      • Taylor R.C.
      • Hetz C.
      Mastering organismal aging through the endoplasmic reticulum proteostasis network.
      ). In contrast, measurement of the biochemical activity of the proteasome, CMA, or autophagy pathways revealed impaired function during aging (
      • Hipp M.S.
      • Kasturi P.
      • Hartl F.U.
      The proteostasis network and its decline in ageing.
      ;
      • Kaushik S.
      • Cuervo A.M.
      Proteostasis and aging.
      ). It may be feasible that slow-progressing damage to the proteome or a particular component of the proteostatic machinery triggers an “hormesis reaction” that reconfigures the network to adjust and adapt, making cells resistant to exogenous acute stress. Alternatively, age-related perturbations, like oxidative stress, may directly alter the function of stress sensors as described for the UPR (
      • Nakato R.
      • Ohkubo Y.
      • Konishi A.
      • Shibata M.
      • Kaneko Y.
      • Iwawaki T.
      • Nakamura T.
      • Lipton S.A.
      • Uehara T.
      Regulation of the unfolded protein response via S-nitrosylation of sensors of endoplasmic reticulum stress.
      ;
      • Cabral-Miranda F.
      • Tamburini G.
      • Martinez G.
      • Medinas M.
      • Gerakis Y.
      • Miedema T.
      • Duran-Aniotz C.
      • Ardiles O.A.
      • Gonzalez C.
      • Sabusap C.
      • BermedoGarcia F.
      • Adamson S.
      • Vitangcol K.
      • Huerta H.
      • Zhang X.
      • Nakamura T.
      • Sardi S.P.
      • Lipton S.A.
      • Kenedy B.K.
      • Hetz C.
      Control of mammalian brain aging by the unfolded protein response (UPR).
      ).
      Different reports have suggested that neurons are highly vulnerable to perturbations to the folding machinery. Human genetic associations have indicated that despite the ubiquitous expression of small HSP (Box 1), mutations in these genes result in the development of motor diseases (
      • Vendredy L.
      • Adriaenssens E.
      • Timmerman V.
      Small heat shock proteins in neurodegenerative diseases.
      ). Mutations in SIL1 (an adenine nucleotide exchange factor of BiP) are associated with Marinesco-Sjögren syndrome, a condition that causes cerebellar ataxia, mental retardation, and muscle weakness. Rare mutations in genes encoding protein disulfide isomerases (Box 2) are also proposed as risk factors for ALS (
      • Woehlbier U.
      • Colombo A.
      • Saaranen M.J.
      • Pérez V.
      • Ojeda J.
      • Bustos F.J.
      • Andreu C.I.
      • Torres M.
      • Valenzuela V.
      • Medinas D.B.
      • et al.
      ALS-linked protein disulfide isomerase variants cause motor dysfunction.
      ), and overexpression of ER57 is protective in preclinical models (
      • Rozas P.
      • Pinto C.
      • Martínez Traub F.
      • Díaz R.
      • Pérez V.
      • Becerra D.
      • Ojeda P.
      • Ojeda J.
      • Wright M.T.
      • Mella J.
      • et al.
      Protein disulfide isomerase ERp57 protects early muscle denervation in experimental ALS.
      ). Experimental targeting of whole-body BiP expression in mice results in specific phenotypes altering motoneuron proteostasis (
      • Jin H.
      • Mimura N.
      • Kashio M.
      • Koseki H.
      • Aoe T.
      Late-onset of spinal neurodegeneration in knock-in mice expressing a mutant BiP.
      ). Also, calnexin deficiency results in selective defects in axonal myelination associated with reduced axonal conductivity (
      • Denzel A.
      • Molinari M.
      • Trigueros C.
      • Martin J.E.
      • Velmurgan S.
      • Brown S.
      • Stamp G.
      • Owen M.J.
      Early postnatal death and motor disorders in mice congenitally deficient in calnexin expression.
      ;
      • Kraus A.
      • Groenendyk J.
      • Bedard K.
      • Baldwin T.A.
      • Krause K.H.
      • Dubois-Dauphin M.
      • Dyck J.
      • Rosenbaum E.E.
      • Korngut L.
      • Colley N.J.
      • et al.
      Calnexin deficiency leads to dysmyelination.
      ). These studies highlight the need for specific folding requirements to sustain the function of specific neuronal subpopulations. Future efforts are needed to identify the critical clients of the proteostasis network that drive neuronal dysfunction when these pathways are altered in disease.
      There are important misconceptions in the field that need to be clarified. It is often assumed that the accumulation of protein aggregates in the brain of patients is sensed by the cell as a “stress signal” because they engage central stress pathways specialized to detected misfolded proteins. This simplistic view does not fit with a lack of correlation between the site where disease-related proteins accumulate and the stress pathways they engage. As discussed here, multiple studies have uncovered possible disease mechanisms involving a direct alteration of key modules of the proteostasis network by disease-related proteins (UPR, HSF1, and autophagy) (Figure 4). The fact that ER stress is among the most common and transversal pathological responses in neurodegenerative diseases suggests that general perturbations to the secretory pathway may result in suboptimal production of essential synaptic proteins, resulting in neuronal dysfunction. This concept suggests a therapeutic opportunity, because it reveals a temporal window for disease intervention before neurons undergo cell death. Since the initiation of most neurodegenerative diseases involves synaptic alterations and loss of connectivity, early diagnosis is needed to successfully test proteostasis-related interventions with success in the clinic. A second layer of complexity has emerged where the spreading of pathological protein aggregates involves several barriers where the proteostasis network may be relevant, including the seeding mechanisms that amplify the content of protein aggregates, the rupture of fibrillar structures and their secretion and transfer to other cells, in addition to extracellular quality control and clearance pathways (
      • Soto C.
      • Pritzkow S.
      Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases.
      ). Thus, defects in the activity of the proteostasis network may determine the threshold for critical damage to trigger degeneration.
      Another aspect that needs to be systematically explored is the specific contribution of proteostasis modules to different cell types of the brain. The diversity of neuronal identities implies distinct gene expression patterns that may also underlie their differential vulnerability to undergo neurodegeneration. It is becoming clear that cells with high demands of protein production, such as Schwann cells and oligodendrocytes, suffer from basal physiological stress and require robust proteostasis mechanisms for optimal function. Cells with complex dendritic arborization, like dopaminergic neurons, or those with extremely long axons, like motoneurons, are also highly susceptible to proteostasis alterations, which may be related to the need to regulate proteostasis from a distance.
      Cell-non-autonomous control of the proteostasis machinery may have an origin in primitive multicellular organisms, where the correlation between environmental changes and adaptive cellular responses was intimate to ensure survival. In mammals, our perception and senses are the window to the outside world. The recently discovered connections among food perception, hypothalamic function, and metabolic regulation may be the first hint in favor of this concept. In this line, the nervous system represents the optimal hub to integrate information and detect very minor fluctuations in homeostasis (temperature changes for example) and propagate signals to the rest of the body to adapt and ensure survival. Thus, the induction of these pathways in neurons may operate as “surveillance mechanisms” that emanate danger signals to preadapt the organism and prepare for further damage. This may also explain why proteostasis-related interventions have dramatic consequences in alleviating brain diseases in experimental models and extend lifespan across species. The mechanisms that engage cell-non-autonomous control of proteostasis need to de further defined. Are these adaptive pathways activated at distance by signaling events in the absence of stress? It may be feasible that posttranslational modification via signaling events engages these stress sensors directly. The same important question remains open to define the involvement of the IRS, the UPR, and HSF1 in normal brain physiology. Which of these adaptive pathways are engaged by a physiologically relevant stimulus in neurons (e.g., experience, perception, depolarization, and growth factors)? Does this activation occur in the absence of protein misfolding? The link between the activity of these proteostasis pathways and the regulation of synaptic activity may be the result of a novel mechanism that emerged during evolution to regulate gene expression and adjust the local requirements to remodel protein composition in synapses under conditions where protein misfolding stress is marginal. Finally, although data relating the UPRmt and neurophysiology are not available, the recent discovery of central components that regulate the pathway will open the possibility of performing extensive studies to address this question using genetically modified mice.
      Overall, available data suggest that strategies to boost the proteostatic capacity of the brain may translate into beneficial effects beyond stress mitigation, highlighting the production of synaptic proteins, neurogenesis, the regulation of connectivity, and neuroinflammation (Figure 4). Many small molecules are under development to target and enhance the activity of adaptive components of the proteostasis network that show remarkable beneficial effects in models of brain diseases. However, the possible future application of these drugs to human treatment should be made with caution, because the proteostasis network has essential roles in the physiology of every tissue of our body. As discussed here, gene therapy may emerge as an alternative to locally engage adaptive mechanisms by delivering master regulators of these pathways (i.e., HSF1, XBP1s, ATF6f, and TFEB) to the specific brain areas affected in a particular disease (Figure 4).
      Finally, when I was preparing this article, I realized that defining the limits of the proteostasis network landscape is very difficult, since primary and secondary modules exist that expand through the whole biology of the cell. Crosstalk and interdependency between many components of the network are reported, but more importantly, sustaining a healthy and functional proteome requires most components of the cell. This includes the regulation of energy metabolism, DNA stability, lipid production, calcium homeostasis, organelle biogenesis, inter-organelle communication platforms, nuclear import/export, intercellular communication mechanisms, and the maintenance of proteostasis in every cellular compartment. This grounds on the fact that proteostasis maintenance is at the core of the autopoietic organization of the cell, determined by the dynamic interdependency between its constituents. The exponential growth of the field is remarkable, where more and more independent validations are available demonstrating the benefits of improving brain proteostasis as a transversal strategy to treat brain diseases, ranging from developmental to psychiatric to neurodegenerative conditions.

      Acknowledgments

      I thank Dr. Hery Urra for figure design and Drs. Like Wisseman, Eric Chevet, Fabiola Osorio, Fabio Martinon, and Eugenia Morselli for conceptual insights and feedback. I apologize to all of the authors whose work could not be cited here because of space limitations. This work was supported by ANID/FONDAP program 15150012, Millenium Institute grant P09-015-F , FONDEF grants ID16I10223 and D11E1007 , FONDECYT grant 1180186 , Ecos-Conicyt grant C17S02 , U.S. Air Force Office of Scientific Research grant 20RT0419 , and Michael J. Fox Foundation (Parkinson’s research target grant ID 12473.01 ).

      Declaration of interests

      C.H. is co-inventor on several patents for gene therapy targeting proteostasis, some of which are licensed to Handl Therapeutics. C.H. has a service contract with Handl Therapeutics to further develop these technologies.

      References

        • Anderson N.S.
        • Haynes C.M.
        Folding the Mitochondrial UPR into the Integrated Stress Response.
        Trends Cell Biol. 2020; 30: 428-439
        • Bajaj L.
        • Lotfi P.
        • Pal R.
        • Ronza A.D.
        • Sharma J.
        • Sardiello M.
        Lysosome biogenesis in health and disease.
        J. Neurochem. 2019; 148: 573-589
        • Balch W.E.
        • Morimoto R.I.
        • Dillin A.
        • Kelly J.W.
        Adapting proteostasis for disease intervention.
        Science. 2008; 319: 916-919
        • Bankston A.N.
        • Forston M.D.
        • Howard R.M.
        • Andres K.R.
        • Smith A.E.
        • Ohri S.S.
        • Bates M.L.
        • Bunge M.B.
        • Whittemore S.R.
        Autophagy is essential for oligodendrocyte differentiation, survival, and proper myelination.
        Glia. 2019; 67: 1745-1759
        • Blackwood E.A.
        • Azizi K.
        • Thuerauf D.J.
        • Paxman R.J.
        • Plate L.
        • Kelly J.W.
        • Wiseman R.L.
        • Glembotski C.C.
        Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis.
        Nat. Commun. 2019; 10: 187
        • Boland B.
        • Yu W.H.
        • Corti O.
        • Mollereau B.
        • Henriques A.
        • Bezard E.
        • Pastores G.M.
        • Rubinsztein D.C.
        • Nixon R.A.
        • Duchen M.R.
        • et al.
        Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.
        Nat. Rev. Drug Discov. 2018; 17: 660-688
        • Brandt C.
        • Nolte H.
        • Henschke S.
        • Engström Ruud L.
        • Awazawa M.
        • Morgan D.A.
        • Gabel P.
        • Sprenger H.G.
        • Hess M.E.
        • Günther S.
        • et al.
        Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation.
        Cell. 2018; 175: 1321-1335.e20
        • Bugallo R.
        • Marlin E.
        • Baltanás A.
        • Toledo E.
        • Ferrero R.
        • Vinueza-Gavilanes R.
        • Larrea L.
        • Arrasate M.
        • Aragón T.
        Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis.
        Cell Death Dis. 2020; 11: 397
        • Bulleid N.J.
        Disulfide bond formation in the mammalian endoplasmic reticulum.
        Cold Spring Harb. Perspect. Biol. 2012; 4: 4
        • Cabral-Miranda F.
        • Tamburini G.
        • Martinez G.
        • Medinas M.
        • Gerakis Y.
        • Miedema T.
        • Duran-Aniotz C.
        • Ardiles O.A.
        • Gonzalez C.
        • Sabusap C.
        • BermedoGarcia F.
        • Adamson S.
        • Vitangcol K.
        • Huerta H.
        • Zhang X.
        • Nakamura T.
        • Sardi S.P.
        • Lipton S.A.
        • Kenedy B.K.
        • Hetz C.
        Control of mammalian brain aging by the unfolded protein response (UPR).
        bioRxiv. 2020; https://doi.org/10.1101/2020.04.13.039172
        • Cagnetta R.
        • Wong H.H.
        • Frese C.K.
        • Mallucci G.R.
        • Krijgsveld J.
        • Holt C.E.
        Noncanonical Modulation of the eIF2 Pathway Controls an Increase in Local Translation during Neural Wiring.
        Mol. Cell. 2019; 73: 474-489.e5
        • Campisi J.
        • Kapahi P.
        • Lithgow G.J.
        • Melov S.
        • Newman J.C.
        • Verdin E.
        From discoveries in ageing research to therapeutics for healthy ageing.
        Nature. 2019; 571: 183-192
        • Chen Y.
        • Wang B.
        • Liu D.
        • Li J.J.
        • Xue Y.
        • Sakata K.
        • Zhu L.Q.
        • Heldt S.A.
        • Xu H.
        • Liao F.F.
        Hsp90 chaperone inhibitor 17-AAG attenuates Aβ-induced synaptic toxicity and memory impairment.
        J. Neurosci. 2014; 34: 2464-2470
        • Chung C.Y.
        • Khurana V.
        • Auluck P.K.
        • Tardiff D.F.
        • Mazzulli J.R.
        • Soldner F.
        • Baru V.
        • Lou Y.
        • Freyzon Y.
        • Cho S.
        • et al.
        Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons.
        Science. 2013; 342: 983-987
        • Cooper A.A.
        • Gitler A.D.
        • Cashikar A.
        • Haynes C.M.
        • Hill K.J.
        • Bhullar B.
        • Liu K.
        • Xu K.
        • Strathearn K.E.
        • Liu F.
        • et al.
        Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models.
        Science. 2006; 313: 324-328
        • Costa-Mattioli M.
        • Walter P.
        The integrated stress response: From mechanism to disease.
        Science. 2020; 368: eaat5314
        • Costa-Mattioli M.
        • Gobert D.
        • Harding H.
        • Herdy B.
        • Azzi M.
        • Bruno M.
        • Bidinosti M.
        • Ben Mamou C.
        • Marcinkiewicz E.
        • Yoshida M.
        • et al.
        Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2.
        Nature. 2005; 436: 1166-1173
        • Costa-Mattioli M.
        • Gobert D.
        • Stern E.
        • Gamache K.
        • Colina R.
        • Cuello C.
        • Sossin W.
        • Kaufman R.
        • Pelletier J.
        • Rosenblum K.
        • et al.
        eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory.
        Cell. 2007; 129: 195-206
        • Das I.
        • Krzyzosiak A.
        • Schneider K.
        • Wrabetz L.
        • D’Antonio M.
        • Barry N.
        • Sigurdardottir A.
        • Bertolotti A.
        Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit.
        Science. 2015; 348: 239-242
        • Decressac M.
        • Mattsson B.
        • Weikop P.
        • Lundblad M.
        • Jakobsson J.
        • Björklund A.
        TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity.
        Proc. Natl. Acad. Sci. USA. 2013; 110: E1817-E1826
        • Denzel A.
        • Molinari M.
        • Trigueros C.
        • Martin J.E.
        • Velmurgan S.
        • Brown S.
        • Stamp G.
        • Owen M.J.
        Early postnatal death and motor disorders in mice congenitally deficient in calnexin expression.
        Mol. Cell. Biol. 2002; 22: 7398-7404
        • Duennwald M.L.
        • Lindquist S.
        Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity.
        Genes Dev. 2008; 22: 3308-3319
        • Ellgaard L.
        • Helenius A.
        Quality control in the endoplasmic reticulum.
        Nat. Rev. Mol. Cell Biol. 2003; 4: 181-191
        • Ellgaard L.
        • Ruddock L.W.
        The human protein disulphide isomerase family: substrate interactions and functional properties.
        EMBO Rep. 2005; 6: 28-32
        • Esk C.
        • Lindenhofer D.
        • Haendeler S.
        • Wester R.A.
        • Pflug F.
        • Schroeder B.
        • Bagley J.A.
        • Elling U.
        • Zuber J.
        • von Haeseler A.
        • Knoblich J.A.
        A human tissue screen identifies a regulator of ER secretion as a brain-size determinant.
        Science. 2020; 370: 935-941
        • Faust O.
        • Rosenzweig R.
        Structural and Biochemical Properties of Hsp40/Hsp70 Chaperone System.
        Adv. Exp. Med. Biol. 2020; 1243: 3-20
        • Fessler E.
        • Eckl E.M.
        • Schmitt S.
        • Mancilla I.A.
        • Meyer-Bender M.F.
        • Hanf M.
        • Philippou-Massier J.
        • Krebs S.
        • Zischka H.
        • Jae L.T.
        A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol.
        Nature. 2020; 579: 433-437
        • Filézac de L’Etang A.
        • Maharjan N.
        • Cordeiro Braña M.
        • Ruegsegger C.
        • Rehmann R.
        • Goswami A.
        • Roos A.
        • Troost D.
        • Schneider B.L.
        • Weis J.
        • Saxena S.
        Marinesco-Sjögren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS.
        Nat. Neurosci. 2015; 18: 227-238
        • Fleming A.
        • Rubinsztein D.C.
        Autophagy in Neuronal Development and Plasticity.
        Trends Neurosci. 2020; 43: 767-779
        • Frakes A.E.
        • Metcalf M.G.
        • Tronnes S.U.
        • Bar-Ziv R.
        • Durieux J.
        • Gildea H.K.
        • Kandahari N.
        • Monshietehadi S.
        • Dillin A.
        Four glial cells regulate ER stress resistance and longevity via neuropeptide signaling in C. elegans.
        Science. 2020; 367: 436-440
        • Fujimoto M.
        • Takaki E.
        • Hayashi T.
        • Kitaura Y.
        • Tanaka Y.
        • Inouye S.
        • Nakai A.
        Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models.
        J. Biol. Chem. 2005; 280: 34908-34916
        • García-Huerta P.
        • Troncoso-Escudero P.
        • Wu D.
        • Thiruvalluvan A.
        • Cisternas-Olmedo M.
        • Henríquez D.R.
        • Plate L.
        • Chana-Cuevas P.
        • Saquel C.
        • Thielen P.
        • et al.
        Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates.
        Acta Neuropathol. 2020; 140: 737-764
        • Gerakis Y.
        • Hetz C.
        Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer’s disease.
        FEBS J. 2018; 285: 995-1011
        • Glatigny M.
        • Moriceau S.
        • Rivagorda M.
        • Ramos-Brossier M.
        • Nascimbeni A.C.
        • Lante F.
        • Shanley M.R.
        • Boudarene N.
        • Rousseaud A.
        • Friedman A.K.
        • et al.
        Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline.
        Curr. Biol. 2019; 29: 435-448.e8
        • Gomez-Pastor R.
        • Burchfiel E.T.
        • Neef D.W.
        • Jaeger A.M.
        • Cabiscol E.
        • McKinstry S.U.
        • Doss A.
        • Aballay A.
        • Lo D.C.
        • Akimov S.S.
        • et al.
        Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s disease.
        Nat. Commun. 2017; 8: 14405
        • Gomez-Pastor R.
        • Burchfiel E.T.
        • Thiele D.J.
        Regulation of heat shock transcription factors and their roles in physiology and disease.
        Nat. Rev. Mol. Cell Biol. 2018; 19: 4-19
        • Gully J.C.
        • Sergeyev V.G.
        • Bhootada Y.
        • Mendez-Gomez H.
        • Meyers C.A.
        • Zolotukhin S.
        • Gorbatyuk M.S.
        • Gorbatyuk O.S.
        Up-regulation of activating transcription factor 4 induces severe loss of dopamine nigral neurons in a rat model of Parkinson’s disease.
        Neurosci. Lett. 2016; 627: 36-41
        • Guo X.
        • Aviles G.
        • Liu Y.
        • Tian R.
        • Unger B.A.
        • Lin Y.T.
        • Wiita A.P.
        • Xu K.
        • Correia M.A.
        • Kampmann M.
        Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.
        Nature. 2020; 579: 427-432
        • Halliday M.
        • Radford H.
        • Sekine Y.
        • Moreno J.
        • Verity N.
        • le Quesne J.
        • Ortori C.A.
        • Barrett D.A.
        • Fromont C.
        • Fischer P.M.
        • et al.
        Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity.
        Cell Death Dis. 2015; 6: e1672
        • Halliday M.
        • Radford H.
        • Zents K.A.M.
        • Molloy C.
        • Moreno J.A.
        • Verity N.C.
        • Smith E.
        • Ortori C.A.
        • Barrett D.A.
        • Bushell M.
        • Mallucci G.R.
        Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice.
        Brain. 2017; 140: 1768-1783
        • Hara T.
        • Nakamura K.
        • Matsui M.
        • Yamamoto A.
        • Nakahara Y.
        • Suzuki-Migishima R.
        • Yokoyama M.
        • Mishima K.
        • Saito I.
        • Okano H.
        • Mizushima N.
        Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice.
        Nature. 2006; 441: 885-889
        • Hartl F.U.
        • Bracher A.
        • Hayer-Hartl M.
        Molecular chaperones in protein folding and proteostasis.
        Nature. 2011; 475: 324-332
        • Hashimoto-Torii K.
        • Torii M.
        • Fujimoto M.
        • Nakai A.
        • El Fatimy R.
        • Mezger V.
        • Ju M.J.
        • Ishii S.
        • Chao S.H.
        • Brennand K.J.
        • et al.
        Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders.
        Neuron. 2014; 82: 560-572
        • Hayashi A.
        • Kasahara T.
        • Kametani M.
        • Kato T.
        Attenuated BDNF-induced upregulation of GABAergic markers in neurons lacking Xbp1.
        Biochem. Biophys. Res. Commun. 2008; 376: 758-763
        • Hernandez D.
        • Torres C.A.
        • Setlik W.
        • Cebrián C.
        • Mosharov E.V.
        • Tang G.
        • Cheng H.C.
        • Kholodilov N.
        • Yarygina O.
        • Burke R.E.
        • et al.
        Regulation of presynaptic neurotransmission by macroautophagy.
        Neuron. 2012; 74: 277-284
        • Hetz C.
        • Saxena S.
        ER stress and the unfolded protein response in neurodegeneration.
        Nat. Rev. Neurol. 2017; 13: 477-491
        • Hetz C.
        • Lee A.H.
        • Gonzalez-Romero D.
        • Thielen P.
        • Castilla J.
        • Soto C.
        • Glimcher L.H.
        Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis.
        Proc. Natl. Acad. Sci. USA. 2008; 105: 757-762
        • Hetz C.
        • Thielen P.
        • Matus S.
        • Nassif M.
        • Court F.
        • Kiffin R.
        • Martinez G.
        • Cuervo A.M.
        • Brown R.H.
        • Glimcher L.H.
        XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy.
        Genes Dev. 2009; 23: 2294-2306
        • Hetz C.
        • Axten J.M.
        • Patterson J.B.
        Pharmacological targeting of the unfolded protein response for disease intervention.
        Nat. Chem. Biol. 2019; 15: 764-775
        • Hetz C.
        • Zhang K.
        • Kaufman R.J.
        Mechanisms, regulation and functions of the unfolded protein response.
        Nat. Rev. Mol. Cell Biol. 2020; 21: 421-438
        • Hipp M.S.
        • Kasturi P.
        • Hartl F.U.
        The proteostasis network and its decline in ageing.
        Nat. Rev. Mol. Cell Biol. 2019; 20: 421-435
        • Hooper P.L.
        • Durham H.D.
        • Török Z.
        • Hooper P.L.
        • Crul T.
        • Vígh L.
        The central role of heat shock factor 1 in synaptic fidelity and memory consolidation.
        Cell Stress Chaperones. 2016; 21: 745-753
        • Ingenwerth M.
        • Estrada V.
        • Stahr A.
        • Müller H.W.
        • von Gall C.
        HSF1-deficiency affects gait coordination and cerebellar calbindin levels.
        Behav. Brain Res. 2016; 310: 103-108
        • Ingenwerth M.
        • Noichl E.
        • Stahr A.
        • Korf H.W.
        • Reinke H.
        • von Gall C.
        Heat Shock Factor 1 Deficiency Affects Systemic Body Temperature Regulation.
        Neuroendocrinology. 2016; 103: 605-615
        • Jayaraj G.G.
        • Hipp M.S.
        • Hartl F.U.
        Functional Modules of the Proteostasis Network.
        Cold Spring Harb. Perspect. Biol. 2020; 12: 12
        • Jin H.
        • Mimura N.
        • Kashio M.
        • Koseki H.
        • Aoe T.
        Late-onset of spinal neurodegeneration in knock-in mice expressing a mutant BiP.
        PLoS ONE. 2014; 9: e112837
        • Kampinga H.H.
        • Craig E.A.
        The HSP70 chaperone machinery: J proteins as drivers of functional specificity.
        Nat. Rev. Mol. Cell Biol. 2010; 11: 579-592
        • Karagöz G.E.
        • Acosta-Alvear D.
        • Walter P.
        The Unfolded Protein Response: Detecting and Responding to Fluctuations in the Protein-Folding Capacity of the Endoplasmic Reticulum.
        Cold Spring Harb. Perspect. Biol. 2019; 11: a033886
        • Kaushik S.
        • Cuervo A.M.
        Proteostasis and aging.
        Nat. Med. 2015; 21: 1406-1415
        • Kaushik S.
        • Cuervo A.M.
        The coming of age of chaperone-mediated autophagy.
        Nat. Rev. Mol. Cell Biol. 2018; 19: 365-381
        • Kim E.
        • Sakata K.
        • Liao F.F.
        Bidirectional interplay of HSF1 degradation and UPR activation promotes tau hyperphosphorylation.
        PLoS Genet. 2017; 13: e1006849
        • Kim H.J.
        • Cho M.H.
        • Shim W.H.
        • Kim J.K.
        • Jeon E.Y.
        • Kim D.H.
        • Yoon S.Y.
        Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects.
        Mol. Psychiatry. 2017; 22: 1576-1584
        • Klaips C.L.
        • Jayaraj G.G.
        • Hartl F.U.
        Pathways of cellular proteostasis in aging and disease.
        J. Cell Biol. 2018; 217: 51-63
        • Kobayashi T.
        • Piao W.
        • Takamura T.
        • Kori H.
        • Miyachi H.
        • Kitano S.
        • Iwamoto Y.
        • Yamada M.
        • Imayoshi I.
        • Shioda S.
        • et al.
        Enhanced lysosomal degradation maintains the quiescent state of neural stem cells.
        Nat. Commun. 2019; 10: 5446
        • Kohl S.
        • Zobor D.
        • Chiang W.C.
        • Weisschuh N.
        • Staller J.
        • Gonzalez Menendez I.
        • Chang S.
        • Beck S.C.
        • Garcia Garrido M.
        • Sothilingam V.
        • et al.
        Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.
        Nat. Genet. 2015; 47: 757-765
        • Komatsu M.
        • Waguri S.
        • Chiba T.
        • Murata S.
        • Iwata J.
        • Tanida I.
        • Ueno T.
        • Koike M.
        • Uchiyama Y.
        • Kominami E.
        • Tanaka K.
        Loss of autophagy in the central nervous system causes neurodegeneration in mice.
        Nature. 2006; 441: 880-884
        • Komatsu M.
        • Waguri S.
        • Koike M.
        • Sou Y.S.
        • Ueno T.
        • Hara T.
        • Mizushima N.
        • Iwata J.
        • Ezaki J.
        • Murata S.
        • et al.
        Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice.
        Cell. 2007; 131: 1149-1163
        • Kondo N.
        • Katsuno M.
        • Adachi H.
        • Minamiyama M.
        • Doi H.
        • Matsumoto S.
        • Miyazaki Y.
        • Iida M.
        • Tohnai G.
        • Nakatsuji H.
        • et al.
        Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration.
        Nat. Commun. 2013; 4: 1405
        • Kramer N.J.
        • Haney M.S.
        • Morgens D.W.
        • Jovičić A.
        • Couthouis J.
        • Li A.
        • Ousey J.
        • Ma R.
        • Bieri G.
        • Tsui C.K.
        • et al.
        CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.
        Nat. Genet. 2018; 50: 603-612
        • Kraus A.
        • Groenendyk J.
        • Bedard K.
        • Baldwin T.A.
        • Krause K.H.
        • Dubois-Dauphin M.
        • Dyck J.
        • Rosenbaum E.E.
        • Korngut L.
        • Colley N.J.
        • et al.
        Calnexin deficiency leads to dysmyelination.
        J. Biol. Chem. 2010; 285: 18928-18938
        • Krukowski K.
        • Nolan A.
        • Frias E.S.
        • Boone M.
        • Ureta G.
        • Grue K.
        • Paladini M.S.
        • Elizarraras E.
        • Delgado L.
        • Bernales S.
        • et al.
        Small molecule cognitive enhancer reverses age-related memory decline in mice.
        bioRxiv. 2020; https://doi.org/10.1101/2020.04.13.039677
        • Krzyzosiak A.
        • Sigurdardottir A.
        • Luh L.
        • Carrara M.
        • Das I.
        • Schneider K.
        • Bertolotti A.
        Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B.
        Cell. 2018; 174: 1216-1228.e19
        • Laguesse S.
        • Creppe C.
        • Nedialkova D.D.
        • Prévot P.P.
        • Borgs L.
        • Huysseune S.
        • Franco B.
        • Duysens G.
        • Krusy N.
        • Lee G.
        • et al.
        A Dynamic Unfolded Protein Response Contributes to the Control of Cortical Neurogenesis.
        Dev. Cell. 2015; 35: 553-567
        • Levine B.
        • Kroemer G.
        Biological Functions of Autophagy Genes: A Disease Perspective.
        Cell. 2019; 176: 11-42
        • Li J.
        • Labbadia J.
        • Morimoto R.I.
        Rethinking HSF1 in Stress, Development, and Organismal Health.
        Trends Cell Biol. 2017; 27: 895-905
        • Martínez G.
        • Vidal R.L.
        • Mardones P.
        • Serrano F.G.
        • Ardiles A.O.
        • Wirth C.
        • Valdés P.
        • Thielen P.
        • Schneider B.L.
        • Kerr B.
        • et al.
        Regulation of Memory Formation by the Transcription Factor XBP1.
        Cell Rep. 2016; 14: 1382-1394
        • Martínez G.
        • Khatiwada S.
        • Costa-Mattioli M.
        • Hetz C.
        ER Proteostasis Control of Neuronal Physiology and Synaptic Function.
        Trends Neurosci. 2018; 41: 610-624
        • Martini-Stoica H.
        • Cole A.L.
        • Swartzlander D.B.
        • Chen F.
        • Wan Y.W.
        • Bajaj L.
        • Bader D.A.
        • Lee V.M.Y.
        • Trojanowski J.Q.
        • Liu Z.
        • et al.
        TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading.
        J. Exp. Med. 2018; 215: 2355-2377
        • Mercado G.
        • Castillo V.
        • Soto P.
        • López N.
        • Axten J.M.
        • Sardi S.P.
        • Hoozemans J.J.M.
        • Hetz C.
        Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of Parkinson’s disease.
        Neurobiol. Dis. 2018; 112: 136-148
        • Moreno J.A.
        • Radford H.
        • Peretti D.
        • Steinert J.R.
        • Verity N.
        • Martin M.G.
        • Halliday M.
        • Morgan J.
        • Dinsdale D.
        • Ortori C.A.
        • et al.
        Sustained translational repression by eIF2α-P mediates prion neurodegeneration.
        Nature. 2012; 485: 507-511
        • Moreno J.A.
        • Halliday M.
        • Molloy C.
        • Radford H.
        • Verity N.
        • Axten J.M.
        • Ortori C.A.
        • Willis A.E.
        • Fischer P.M.
        • Barrett D.A.
        • Mallucci G.R.
        Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice.
        Sci. Transl. Med. 2013; 5: 206ra138
        • Morimoto R.I.
        The heat shock response: systems biology of proteotoxic stress in aging and disease.
        Cold Spring Harb. Symp. Quant. Biol. 2011; 76: 91-99
        • Morimoto R.I.
        Cell-Nonautonomous Regulation of Proteostasis in Aging and Disease.
        Cold Spring Harb. Perspect. Biol. 2020; 12: a034074
        • Nakato R.
        • Ohkubo Y.
        • Konishi A.
        • Shibata M.
        • Kaneko Y.
        • Iwawaki T.
        • Nakamura T.
        • Lipton S.A.
        • Uehara T.
        Regulation of the unfolded protein response via S-nitrosylation of sensors of endoplasmic reticulum stress.
        Sci. Rep. 2015; 5: 14812
        • Oakes S.A.
        • Papa F.R.
        The role of endoplasmic reticulum stress in human pathology.
        Annu. Rev. Pathol. 2015; 10: 173-194
        • Obacz J.
        • Avril T.
        • Le Reste P.J.
        • Urra H.
        • Quillien V.
        • Hetz C.
        • Chevet E.
        Endoplasmic reticulum proteostasis in glioblastoma-From molecular mechanisms to therapeutic perspectives.
        Sci. Signal. 2017; 10: 10
        • Okerlund N.D.
        • Schneider K.
        • Leal-Ortiz S.
        • Montenegro-Venegas C.
        • Kim S.A.
        • Garner L.C.
        • Waites C.L.
        • Gundelfinger E.D.
        • Reimer R.J.
        • Garner C.C.
        Bassoon Controls Presynaptic Autophagy through Atg5.
        Neuron. 2018; 97: 727
        • Oliveira M.M.
        • Lourenco M.V.
        • Longo F.
        • Kasica N.P.
        • Yang W.
        • Ureta G.
        • Ferreira D.D.P.
        • Mendonça P.H.J.
        • Bernales S.
        • Ma T.
        • et al.
        Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease.
        Science Signaling. 2021; 14: eabc5429
        • Ounallah-Saad H.
        • Sharma V.
        • Edry E.
        • Rosenblum K.
        Genetic or pharmacological reduction of PERK enhances cortical-dependent taste learning.
        J. Neurosci. 2014; 34: 14624-14632
        • Pakos-Zebrucka K.
        • Koryga I.
        • Mnich K.
        • Ljujic M.
        • Samali A.
        • Gorman A.M.
        The integrated stress response.
        EMBO Rep. 2016; 17: 1374-1395
        • Park S.
        • Aintablian A.
        • Coupe B.
        • Bouret S.G.
        The endoplasmic reticulum stress-autophagy pathway controls hypothalamic development and energy balance regulation in leptin-deficient neonates.
        Nat. Commun. 2020; 11: 1914
        • Pickford F.
        • Masliah E.
        • Britschgi M.
        • Lucin K.
        • Narasimhan R.
        • Jaeger P.A.
        • Small S.
        • Spencer B.
        • Rockenstein E.
        • Levine B.
        • Wyss-Coray T.
        The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice.
        J. Clin. Invest. 2008; 118: 2190-2199
        • Pierce A.
        • Podlutskaya N.
        • Halloran J.J.
        • Hussong S.A.
        • Lin P.Y.
        • Burbank R.
        • Hart M.J.
        • Galvan V.
        Over-expression of heat shock factor 1 phenocopies the effect of chronic inhibition of TOR by rapamycin and is sufficient to ameliorate Alzheimer’s-like deficits in mice modeling the disease.
        J. Neurochem. 2013; 124: 880-893
        • Polito V.A.
        • Li H.
        • Martini-Stoica H.
        • Wang B.
        • Yang L.
        • Xu Y.
        • Swartzlander D.B.
        • Palmieri M.
        • di Ronza A.
        • Lee V.M.
        • et al.
        Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB.
        EMBO Mol. Med. 2014; 6: 1142-1160
        • Prahlad V.
        • Cornelius T.
        • Morimoto R.I.
        Regulation of the cellular heat shock response in Caenorhabditis elegans by thermosensory neurons.
        Science. 2008; 320: 811-814
        • Preissler S.
        • Ron D.
        Early Events in the Endoplasmic Reticulum Unfolded Protein Response.
        Cold Spring Harb. Perspect. Biol. 2019; 11: 11
        • Prudencio M.
        • Belzil V.V.
        • Batra R.
        • Ross C.A.
        • Gendron T.F.
        • Pregent L.J.
        • Murray M.E.
        • Overstreet K.K.
        • Piazza-Johnston A.E.
        • Desaro P.
        • et al.
        Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS.
        Nat. Neurosci. 2015; 18: 1175-1182
        • Rabouw H.H.
        • Langereis M.A.
        • Anand A.A.
        • Visser L.J.
        • de Groot R.J.
        • Walter P.
        • van Kuppeveld F.J.M.
        Small molecule ISRIB suppresses the integrated stress response within a defined window of activation.
        Proc. Natl. Acad. Sci. USA. 2019; 116: 2097-2102
        • Radford H.
        • Moreno J.A.
        • Verity N.
        • Halliday M.
        • Mallucci G.R.
        PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia.
        Acta Neuropathol. 2015; 130: 633-642
        • Rozas P.
        • Pinto C.
        • Martínez Traub F.
        • Díaz R.
        • Pérez V.
        • Becerra D.
        • Ojeda P.
        • Ojeda J.
        • Wright M.T.
        • Mella J.
        • et al.
        Protein disulfide isomerase ERp57 protects early muscle denervation in experimental ALS.
        Acta Neuropathol. Commun. 2021; 9: 21
        • Saftig P.
        • Puertollano R.
        How Lysosomes Sense, Integrate, and Cope with Stress.
        Trends Biochem. Sci. 2020;
        • Sala A.J.
        • Bott L.C.
        • Morimoto R.I.
        Shaping proteostasis at the cellular, tissue, and organismal level.
        J. Cell Biol. 2017; 216: 1231-1241
        • Saraswat Ohri S.
        • Howard R.M.
        • Liu Y.
        • Andres K.R.
        • Shepard C.T.
        • Hetman M.
        • Whittemore S.R.
        Oligodendrocyte-specific deletion of Xbp1 exacerbates the endoplasmic reticulum stress response and restricts locomotor recovery after thoracic spinal cord injury.
        Glia. 2020;
        • Saxena S.
        • Cabuy E.
        • Caroni P.
        A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice.
        Nat. Neurosci. 2009; 12: 627-636
        • Schuck S.
        Microautophagy - distinct molecular mechanisms handle cargoes of many sizes.
        J. Cell Sci. 2020; 133: 133
        • Scrivo A.
        • Bourdenx M.
        • Pampliega O.
        • Cuervo A.M.
        Selective autophagy as a potential therapeutic target for neurodegenerative disorders.
        Lancet Neurol. 2018; 17: 802-815
        • Sharma V.
        • Sood R.
        • Khlaifia A.
        • Eslamizade M.J.
        • Hung T.Y.
        • Lou D.
        • Asgarihafshejani A.
        • Lalzar M.
        • Kiniry S.J.
        • Stokes M.P.
        • et al.
        eIF2α controls memory consolidation via excitatory and somatostatin neurons.
        Nature. 2020; 586: 412-416
        • Sidrauski C.
        • Acosta-Alvear D.
        • Khoutorsky A.
        • Vedantham P.
        • Hearn B.R.
        • Li H.
        • Gamache K.
        • Gallagher C.M.
        • Ang K.K.
        • Wilson C.
        • et al.
        Pharmacological brake-release of mRNA translation enhances cognitive memory.
        eLife. 2013; 2: e00498
        • Smith H.L.
        • Freeman O.J.
        • Butcher A.J.
        • Holmqvist S.
        • Humoud I.
        • Schätzl T.
        • Hughes D.T.
        • Verity N.C.
        • Swinden D.P.
        • Hayes J.
        • et al.
        Astrocyte Unfolded Protein Response Induces a Specific Reactivity State that Causes Non-Cell-Autonomous Neuronal Degeneration.
        Neuron. 2020; 105: 855-866.e5
        • Sossin W.S.
        • Costa-Mattioli M.
        Translational Control in the Brain in Health and Disease.
        Cold Spring Harb. Perspect. Biol. 2019; 11: 11
        • Soto C.
        • Pritzkow S.
        Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases.
        Nat. Neurosci. 2018; 21: 1332-1340
        • Steffen K.K.
        • Dillin A.
        A Ribosomal Perspective on Proteostasis and Aging.
        Cell Metab. 2016; 23: 1004-1012
        • Stern E.
        • Chinnakkaruppan A.
        • David O.
        • Sonenberg N.
        • Rosenblum K.
        Blocking the eIF2α kinase (PKR) enhances positive and negative forms of cortex-dependent taste memory.
        J. Neurosci. 2013; 33: 2517-2525
        • Sun S.
        • Sun Y.
        • Ling S.C.
        • Ferraiuolo L.
        • McAlonis-Downes M.
        • Zou Y.
        • Drenner K.
        • Wang Y.
        • Ditsworth D.
        • Tokunaga S.
        • et al.
        Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS.
        Proc. Natl. Acad. Sci. USA. 2015; 112: E6993-E7002
        • Sun L.O.
        • Mulinyawe S.B.
        • Collins H.Y.
        • Ibrahim A.
        • Li Q.
        • Simon D.J.
        • Tessier-Lavigne M.
        • Barres B.A.
        Spatiotemporal Control of CNS Myelination by Oligodendrocyte Programmed Cell Death through the TFEB-PUMA Axis.
        Cell. 2018; 175 (1811–1826.e1821)
        • Tan X.
        • Du X.
        • Jiang Y.
        • Botchway B.O.A.
        • Hu Z.
        • Fang M.
        Inhibition of Autophagy in Microglia Alters Depressive-Like Behavior via BDNF Pathway in Postpartum Depression.
        Front. Psychiatry. 2018; 9: 434
        • Tatum M.C.
        • Ooi F.K.
        • Chikka M.R.
        • Chauve L.
        • Martinez-Velazquez L.A.
        • Steinbusch H.W.M.
        • Morimoto R.I.
        • Prahlad V.
        Neuronal serotonin release triggers the heat shock response in C. elegans in the absence of temperature increase.
        Curr. Biol. 2015; 25: 163-174
        • Taylor R.C.
        • Dillin A.
        XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity.
        Cell. 2013; 153: 1435-1447
        • Taylor R.C.
        • Hetz C.
        Mastering organismal aging through the endoplasmic reticulum proteostasis network.
        Aging Cell. 2020; 19: e13265
        • Torra A.
        • Parent A.
        • Cuadros T.
        • Rodríguez-Galván B.
        • Ruiz-Bronchal E.
        • Ballabio A.
        • Bortolozzi A.
        • Vila M.
        • Bové J.
        Overexpression of TFEB Drives a Pleiotropic Neurotrophic Effect and Prevents Parkinson’s Disease-Related Neurodegeneration.
        Mol. Ther. 2018; 26: 1552-1567
        • Trinh M.A.
        • Kaphzan H.
        • Wek R.C.
        • Pierre P.
        • Cavener D.R.
        • Klann E.
        Brain-specific disruption of the eIF2α kinase PERK decreases ATF4 expression and impairs behavioral flexibility.
        Cell Rep. 2012; 1: 676-688
        • Uchida S.
        • Hara K.
        • Kobayashi A.
        • Fujimoto M.
        • Otsuki K.
        • Yamagata H.
        • Hobara T.
        • Abe N.
        • Higuchi F.
        • Shibata T.
        • et al.
        Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1.
        Proc. Natl. Acad. Sci. USA. 2011; 108: 1681-1686
        • Urra H.
        • Henriquez D.R.
        • Cánovas J.
        • Villarroel-Campos D.
        • Carreras-Sureda A.
        • Pulgar E.
        • Molina E.
        • Hazari Y.M.
        • Limia C.M.
        • Alvarez-Rojas S.
        • et al.
        IRE1α governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A.
        Nat. Cell Biol. 2018; 20: 942-953
        • Valdés P.
        • Mercado G.
        • Vidal R.L.
        • Molina C.
        • Parsons G.
        • Court F.A.
        • Martinez A.
        • Galleguillos D.
        • Armentano D.
        • Schneider B.L.
        • Hetz C.
        Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1.
        Proc. Natl. Acad. Sci. USA. 2014; 111: 6804-6809
        • Valenzuela V.
        • Collyer E.
        • Armentano D.
        • Parsons G.B.
        • Court F.A.
        • Hetz C.
        Activation of the unfolded protein response enhances motor recovery after spinal cord injury.
        Cell Death Dis. 2012; 3: e272
        • Valenzuela V.
        • Jackson K.L.
        • Sardi S.P.
        • Hetz C.
        Gene Therapy Strategies to Restore ER Proteostasis in Disease.
        Mol. Ther. 2018; 26: 1404-1413
        • Vendredy L.
        • Adriaenssens E.
        • Timmerman V.
        Small heat shock proteins in neurodegenerative diseases.
        Cell Stress Chaperones. 2020; 25: 679-699
        • Vidal R.L.
        • Figueroa A.
        • Court F.A.
        • Thielen P.
        • Molina C.
        • Wirth C.
        • Caballero B.
        • Kiffin R.
        • Segura-Aguilar J.
        • Cuervo A.M.
        • et al.
        Targeting the UPR transcription factor XBP1 protects against Huntington’s disease through the regulation of FoxO1 and autophagy.
        Hum. Mol. Genet. 2012; 21: 2245-2262
        • Vidal R.L.
        • Sepulveda D.
        • Troncoso-Escudero P.
        • Garcia-Huerta P.
        • Gonzalez C.
        • Plate L.
        • Jerez C.
        • Canovas J.
        • Rivera C.A.
        • Castillo V.
        • et al.
        Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration.
        Mol. Ther. 2021; (Published online February 3, 2021)https://doi.org/10.1016/j.ymthe.2021.01.033
        • Wang M.
        • Kaufman R.J.
        Protein misfolding in the endoplasmic reticulum as a conduit to human disease.
        Nature. 2016; 529: 326-335
        • Wang B.
        • Liu Y.
        • Huang L.
        • Chen J.
        • Li J.J.
        • Wang R.
        • Kim E.
        • Chen Y.
        • Justicia C.
        • Sakata K.
        • et al.
        A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer’s mouse model via an HSF1-mediated mechanism.
        Mol. Psychiatry. 2017; 22: 990-1001
        • Way S.W.
        • Popko B.
        Harnessing the integrated stress response for the treatment of multiple sclerosis.
        Lancet Neurol. 2016; 15: 434-443
        • Wheeler M.A.
        • Jaronen M.
        • Covacu R.
        • Zandee S.E.J.
        • Scalisi G.
        • Rothhammer V.
        • Tjon E.C.
        • Chao C.C.
        • Kenison J.E.
        • Blain M.
        • et al.
        Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation.
        Cell. 2019; 176: 581-596.e18
        • Wilhelm B.G.
        • Mandad S.
        • Truckenbrodt S.
        • Kröhnert K.
        • Schäfer C.
        • Rammner B.
        • Koo S.J.
        • Claßen G.A.
        • Krauss M.
        • Haucke V.
        • et al.
        Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins.
        Science. 2014; 344: 1023-1028
        • Williams K.W.
        • Liu T.
        • Kong X.
        • Fukuda M.
        • Deng Y.
        • Berglund E.D.
        • Deng Z.
        • Gao Y.
        • Liu T.
        • Sohn J.W.
        • et al.
        Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis.
        Cell Metab. 2014; 20: 471-482
        • Woehlbier U.
        • Colombo A.
        • Saaranen M.J.
        • Pérez V.
        • Ojeda J.
        • Bustos F.J.
        • Andreu C.I.
        • Torres M.
        • Valenzuela V.
        • Medinas D.B.
        • et al.
        ALS-linked protein disulfide isomerase variants cause motor dysfunction.
        EMBO J. 2016; 35: 845-865
        • Xiao Q.
        • Yan P.
        • Ma X.
        • Liu H.
        • Perez R.
        • Zhu A.
        • Gonzales E.
        • Burchett J.M.
        • Schuler D.R.
        • Cirrito J.R.
        • et al.
        Enhancing astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis.
        J. Neurosci. 2014; 34: 9607-9620
        • Xiao Q.
        • Yan P.
        • Ma X.
        • Liu H.
        • Perez R.
        • Zhu A.
        • Gonzales E.
        • Tripoli D.L.
        • Czerniewski L.
        • Ballabio A.
        • et al.
        Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing Aβ Generation and Amyloid Plaque Pathogenesis.
        J. Neurosci. 2015; 35: 12137-12151
        • Xiao Y.
        • Deng Y.
        • Yuan F.
        • Xia T.
        • Liu H.
        • Li Z.
        • Chen S.
        • Liu Z.
        • Ying H.
        • Liu Y.
        • et al.
        An ATF4-ATG5 signaling in hypothalamic POMC neurons regulates obesity.
        Autophagy. 2017; 13: 1088-1089
        • Xilouri M.
        • Brekk O.R.
        • Landeck N.
        • Pitychoutis P.M.
        • Papasilekas T.
        • Papadopoulou-Daifoti Z.
        • Kirik D.
        • Stefanis L.
        Boosting chaperone-mediated autophagy in vivo mitigates α-synuclein-induced neurodegeneration.
        Brain. 2013; 136: 2130-2146
        • Yan J.
        • Porch M.W.
        • Court-Vazquez B.
        • Bennett M.V.L.
        • Zukin R.S.
        Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice.
        Proc. Natl. Acad. Sci. USA. 2018; 115: E9707-E9716
        • You K.
        • Wang L.
        • Chou C.H.
        • Liu K.
        • Nakata T.
        • Jaiswal A.
        • Yao J.
        • Lefkovith A.
        • Omar A.
        • Perrigoue J.G.
        • et al.
        QRICH1 dictates the outcome of ER stress through transcriptional control of proteostasis.
        Science. 2021; 371: eabb6896
        • Zhu P.J.
        • Huang W.
        • Kalikulov D.
        • Yoo J.W.
        • Placzek A.N.
        • Stoica L.
        • Zhou H.
        • Bell J.C.
        • Friedlander M.J.
        • Krnjević K.
        • et al.
        Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition.
        Cell. 2011; 147: 1384-1396
        • Zhu P.J.
        • Khatiwada S.
        • Cui Y.
        • Reineke L.C.
        • Dooling S.W.
        • Kim J.J.
        • Li W.
        • Walter P.
        • Costa-Mattioli M.
        Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome.
        Science. 2019; 366: 843-849