1932

Abstract

As the world's population ages, neurodegenerative disorders are poised to become the commonest cause of death. Despite this, they remain essentially untreatable. Characterized pathologically both by the aggregation of disease-specific misfolded proteins and by changes in cellular stress responses, to date, therapeutic approaches have focused almost exclusively on reducing misfolded protein load—notably amyloid beta (Aβ) in Alzheimer's disease. The repeated failure of clinical trials has led to despondency over the possibility that these disorders will ever be treated. We argue that this is in fact a time for optimism: Targeting various generic stress responses is emerging as an increasingly promising means of modifying disease progression across these disorders. New treatments are approaching clinical trials, while novel means of targeting aggregates could eventually act preventively in early disease.

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2020-10-06
2024-12-13
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Literature Cited

  1. Abisambra JF, Jinwal UK, Blair LJ, O'Leary JC III, Li Q et al. 2013. Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J. Neurosci. 33:9498–507
    [Google Scholar]
  2. Anguiano J, Garner TP, Mahalingam M, Das BC, Gavathiotis E, Cuervo AM 2013. Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives. Nat. Chem. Biol. 9:374–82
    [Google Scholar]
  3. Ashkenazi A, Bento CF, Ricketts T, Vicinanza M, Siddiqi F et al. 2017. Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 545:108–11
    [Google Scholar]
  4. Atkin JD, Farg MA, Walker AK, McLean C, Tomas D, Horne MK 2008. Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis. Neurobiol. Dis. 30:400–7
    [Google Scholar]
  5. Babinchak WM, Surewicz WK. 2020. Liquid–liquid phase separation and its mechanistic role in pathological protein aggregation. J. Mol. Biol. 432:1910–25
    [Google Scholar]
  6. Balducci C, Frasca A, Zotti M, La Vitola P, Mhillaj E et al. 2017. Toll-like receptor 4-dependent glial cell activation mediates the impairment in memory establishment induced by β-amyloid oligomers in an acute mouse model of Alzheimer's disease. Brain Behav. Immun. 60:188–97
    [Google Scholar]
  7. Bayne AN, Trempe JF. 2019. Mechanisms of PINK1, ubiquitin and Parkin interactions in mitochondrial quality control and beyond. Cell. Mol. Life Sci. 76:4589–611
    [Google Scholar]
  8. Bento CF, Ashkenazi A, Jimenez-Sanchez M, Rubinsztein DC 2016a. The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway. Nat. Commun. 7:11803
    [Google Scholar]
  9. Bento CF, Renna M, Ghislat G, Puri C, Ashkenazi A et al. 2016b. Mammalian autophagy: How does it work. ? Annu. Rev. Biochem. 85:685–713
    [Google Scholar]
  10. Berger Z, Ravikumar B, Menzies FM, Oroz LG, Underwood BR et al. 2006. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15:433–42
    [Google Scholar]
  11. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ 2013. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol 125:777–94
    [Google Scholar]
  12. Boland B, Kumar A, Lee S, Platt FM, Wegiel J et al. 2008. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J. Neurosci. 28:6926–37
    [Google Scholar]
  13. Bordi M, Darji S, Sato Y, Mellen M, Berg MJ et al. 2019. mTOR hyperactivation in Down syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy. Cell Death Dis 10:563
    [Google Scholar]
  14. Boya P, González-Polo RA, Casares N, Perfettini JL, Dessen P et al. 2005. Inhibition of macroautophagy triggers apoptosis. Mol. Cell. Biol. 25:1025–40
    [Google Scholar]
  15. Bravo R, Parra V, Gatica D, Rodriguez AE, Torrealba N et al. 2013. Endoplasmic reticulum and the unfolded protein response: dynamics and metabolic integration. Int. Rev. Cell Mol. Biol. 301:215–90
    [Google Scholar]
  16. Caballero B, Wang Y, Diaz A, Tasset I, Juste YR et al. 2018. Interplay of pathogenic forms of human tau with different autophagic pathways. Aging Cell 17:e12692
    [Google Scholar]
  17. Carnemolla A, Fossale E, Agostoni E, Michelazzi S, Calligaris R et al. 2009. Rrs1 is involved in endoplasmic reticulum stress response in Huntington disease. J. Biol. Chem. 284:18167–73
    [Google Scholar]
  18. Celardo I, Costa AC, Lehmann S, Jones C, Wood N et al. 2016. Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease. Cell Death Dis 7:e2271
    [Google Scholar]
  19. Chang MC, Srinivasan K, Friedman BA, Suto E, Modrusan Z et al. 2017. Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation. J. Exp. Med. 214:2611–28
    [Google Scholar]
  20. Cho KJ, Lee BI, Cheon SY, Kim HW, Kim HJ, Kim GW 2009. Inhibition of apoptosis signal-regulating kinase 1 reduces endoplasmic reticulum stress and nuclear huntingtin fragments in a mouse model of Huntington disease. Neuroscience 163:1128–34
    [Google Scholar]
  21. Choi ML, Gandhi S. 2018. Crucial role of protein oligomerization in the pathogenesis of Alzheimer's and Parkinson's diseases. FEBS J 285:3631–44
    [Google Scholar]
  22. Chou A, Krukowski K, Jopson T, Zhu PJ, Costa-Mattioli M et al. 2017. Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. PNAS 114:E642026
    [Google Scholar]
  23. Chowdhury S, Otomo C, Leitner A, Ohashi K, Aebersold R et al. 2018. Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex. PNAS 115:E9792801
    [Google Scholar]
  24. Colacurcio DJ, Pensalfini A, Jiang Y, Nixon RA 2018. Dysfunction of autophagy and endosomal-lysosomal pathways: roles in pathogenesis of Down syndrome and Alzheimer's disease. Free Radic. Biol. Med. 114:40–51
    [Google Scholar]
  25. Colla E, Coune P, Liu Y, Pletnikova O, Troncoso JC et al. 2012. Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo. J. Neurosci. 32:3306–20
    [Google Scholar]
  26. Corbett GT, Wang Z, Hong W, Colom-Cadena M, Rose J et al. 2020. PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins. Acta Neuropathol 139:503–26
    [Google Scholar]
  27. Costa-Mattioli M, Gobert D, Stern E, Gamache K, Colina R et al. 2007. eIF2α phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell 129:195–206
    [Google Scholar]
  28. Cremades N, Cohen SIA, Deas E, Abramov AY, Chen AY et al. 2012. Direct observation of the interconversion of normal and toxic forms of α-synuclein. Cell 149:1048–59
    [Google Scholar]
  29. Cuddy LK, Wani WY, Morella ML, Pitcairn C, Tsutsumi K et al. 2019. Stress-induced cellular clearance is mediated by the SNARE protein ykt6 and disrupted by α-synuclein. Neuron 104:869–84.e11
    [Google Scholar]
  30. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D 2004. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 305:1292–95
    [Google Scholar]
  31. Cummings J, Ritter A, Zhong K 2018. Clinical trials for disease-modifying therapies in Alzheimer's disease: a primer, lessons learned, and a blueprint for the future. J. Alzheimers Dis. 64:S3–22
    [Google Scholar]
  32. Das I, Krzyzosiak A, Schneider K, Wrabetz L, D'Antonio M et al. 2015. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science 348:239–42
    [Google Scholar]
  33. De S, Klenerman D. 2019. Imaging individual protein aggregates to follow aggregation and determine the role of aggregates in neurodegenerative disease. Biochim. Biophys. Acta Proteins Proteom. 1867:870–78
    [Google Scholar]
  34. De S, Whiten DR, Ruggeri FS, Hughes C, Rodrigues M et al. 2019a. Soluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer's disease progression. Acta Neuropathol. Commun. 7:120
    [Google Scholar]
  35. De S, Wirthensohn DC, Flagmeier P, Hughes C, Aprile FA et al. 2019b. Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms. Nat. Commun. 10:1541
    [Google Scholar]
  36. De Strooper B, Karran E 2016. The cellular phase of Alzheimer's disease. Cell 164:603–15
    [Google Scholar]
  37. Deretic V, Levine B. 2018. Autophagy balances inflammation in innate immunity. Autophagy 14:243–51
    [Google Scholar]
  38. Deriziotis P, Andre R, Smith DM, Goold R, Kinghorn KJ et al. 2011. Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry. EMBO J 30:3065–77
    [Google Scholar]
  39. Devi L, Ohno M. 2014. PERK mediates eIF2α phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer's disease. Neurobiol. Aging 35:2272–81
    [Google Scholar]
  40. Djajadikerta A, Keshri S, Pavel M, Prestil R, Ryan L, Rubinsztein DC 2019. Autophagy induction as a therapeutic strategy for neurodegenerative diseases. J. Mol. Biol. 432:2799–821
    [Google Scholar]
  41. Dooley HC, Razi M, Polson HEJ, Girardin SE, Wilson MI, Tooze SA 2014. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12–5-16L1. Mol. Cell 55:238–52
    [Google Scholar]
  42. Drews A, De S, Flagmeier P, Wirthensohn DC, Chen WH et al. 2017. Inhibiting the Ca2+ influx induced by human CSF. Cell Rep 21:3310–16
    [Google Scholar]
  43. Duran-Aniotz C, Cornejo VH, Espinoza S, Ardiles AO, Medinas DB et al. 2017. IRE1 signaling exacerbates Alzheimer's disease pathogenesis. Acta Neuropathol 134:489–506
    [Google Scholar]
  44. Ejlerskov P, Rasmussen I, Nielsen TT, Bergstrom AL, Tohyama Y et al. 2013. Tubulin polymerization-promoting protein (TPPP/p25α) promotes unconventional secretion of α-synuclein through exophagy by impairing autophagosome-lysosome fusion. J. Biol. Chem. 288:17313–35
    [Google Scholar]
  45. Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ et al. 2018. Structures of filaments from Pick's disease reveal a novel tau protein fold. Nature 561:137–40
    [Google Scholar]
  46. Fernández AF, Sebti S, Wei Y, Zou Z, Shi M et al. 2018. Disruption of the beclin 1–BCL2 autophagy regulatory complex promotes longevity in mice. Nature 558:136–40
    [Google Scholar]
  47. François-Moutal L, Perez-Miller S, Scott DD, Miranda VG, Mollasalehi N, Khanna M 2019. Structural insights into TDP-43 and effects of post-translational modifications. Front. Mol. Neurosci 12: 301. Corrigendum. 2020 Front. Mol. Neurosci. 13.45
    [Google Scholar]
  48. Franzmeier N, Rubinski A, Neitzel J, Kim Y, Damm A et al. 2019. Functional connectivity associated with tau levels in ageing, Alzheimer's, and small vessel disease. Brain 142:1093–107
    [Google Scholar]
  49. Fusco G, Chen SW, Williamson PTF, Cascella R, Perni M et al. 2017. Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers. Science 358:1440–43
    [Google Scholar]
  50. Gal J, Strom AL, Kwinter DM, Kilty R, Zhang J et al. 2009. Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism. J. Neurochem. 111:1062–73
    [Google Scholar]
  51. Gambuzza ME, Sofo V, Salmeri FM, Soraci L, Marino S, Bramanti P 2014. Toll-like receptors in Alzheimer's disease: a therapeutic perspective. CNS Neurol. Disord. Drug Targets 13:1542–58
    [Google Scholar]
  52. Gan L, Cookson MR, Petrucelli L, La Spada AR 2018. Converging pathways in neurodegeneration, from genetics to mechanisms. Nat. Neurosci. 21:1300–9
    [Google Scholar]
  53. Goedert M, Eisenberg DS, Crowther RA 2017. Propagation of tau aggregates and neurodegeneration. Annu. Rev. Neurosci. 40:189–210
    [Google Scholar]
  54. Halliday M, Radford H, Sekine Y, Moreno J, Verity N et al. 2015. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis 6:e1672
    [Google Scholar]
  55. Halliday M, Radford H, Zents KAM, Molloy C, Moreno JA et al. 2017. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain 140:1768–83
    [Google Scholar]
  56. Hansen M, Rubinsztein DC, Walker DW 2018. Autophagy as a promoter of longevity: insights from model organisms. Nat. Rev. Mol. Cell Biol. 19:579–93
    [Google Scholar]
  57. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y et al. 2006. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–89
    [Google Scholar]
  58. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R et al. 2000a. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6:1099–108
    [Google Scholar]
  59. Harding HP, Zeng H, Zhang Y, Jungries R, Chung P et al. 2001. Diabetes mellitus and exocrine pancreatic dysfunction in Perk−/− mice reveals a role for translational control in secretory cell survival. Mol. Cell 7:1153–63
    [Google Scholar]
  60. Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D 2000b. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol. Cell 5:897–904
    [Google Scholar]
  61. Hardy J, Selkoe DJ. 2002. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353–56
    [Google Scholar]
  62. Heckmann BL, Green DR. 2019. LC3-associated phagocytosis at a glance. J. Cell Sci. 132:jcs222984
    [Google Scholar]
  63. Heckmann BL, Teubner BJW, Tummers B, Boada-Romero E, Harris L et al. 2019. LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer's disease. Cell 178:536–51.e14
    [Google Scholar]
  64. Hemonnot AL, Hua J, Ulmann L, Hirbec H 2019. Microglia in Alzheimer disease: well-known targets and new opportunities. Front. Aging Neurosci. 11:233
    [Google Scholar]
  65. Hetz C, Axten JM, Patterson JB 2019. Pharmacological targeting of the unfolded protein response for disease intervention. Nat. Chem. Biol. 15:764–75
    [Google Scholar]
  66. Hetz C, Mollereau B. 2014. Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat. Rev. Neurosci. 15:233–49
    [Google Scholar]
  67. Hickman S, Izzy S, Sen P, Morsett L, El Khoury J 2018. Microglia in neurodegeneration. Nat. Neurosci. 21:1359–69
    [Google Scholar]
  68. Hipp MS, Patel CN, Bersuker K, Riley BE, Kaiser SE et al. 2012. Indirect inhibition of 26S proteasome activity in a cellular model of Huntington's disease. J. Cell Biol. 196:573–87
    [Google Scholar]
  69. Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS et al. 2011. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat. Genet. 43:699–705
    [Google Scholar]
  70. Hoozemans JJM, van Haastert ES, Eikelenboom P, de Vos RAI, Rozemuller JM, Scheper W 2007. Activation of the unfolded protein response in Parkinson's disease. Biochem. Biophys. Res. Commun. 354:707–11
    [Google Scholar]
  71. Hoozemans JJM, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W 2009. The unfolded protein response is activated in pretangle neurons in Alzheimer's disease hippocampus. Am. J. Pathol. 174:1241–51
    [Google Scholar]
  72. Hughes C, Choi ML, Yi J-H, Kim S-C, Drews A et al. 2020. Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death. Commun. Biol. 3:79
    [Google Scholar]
  73. Iadanza MG, Jackson MP, Hewitt EW, Ranson NA, Radford SE 2018. A new era for understanding amyloid structures and disease. Nat. Rev. Mol. Cell Biol. 19:755–73
    [Google Scholar]
  74. Iljina M, Garcia GA, Horrocks MH, Tosatto L, Choi ML et al. 2016. Kinetic model of the aggregation of α-synuclein provides insights into prion-like spreading. PNAS 113:E120615
    [Google Scholar]
  75. Ishikawa K, Saiki S, Furuya N, Imamichi Y, Tsuboi Y, Hattori N 2019. p150glued deficiency impairs effective fusion between autophagosomes and lysosomes due to their redistribution to the cell periphery. Neurosci. Lett. 690:181–87
    [Google Scholar]
  76. Ito Y, Yamada M, Tanaka H, Aida K, Tsuruma K et al. 2009. Involvement of CHOP, an ER-stress apoptotic mediator, in both human sporadic ALS and ALS model mice. Neurobiol. Dis. 36:470–76
    [Google Scholar]
  77. Jin J-J, Kim H-D, Maxwell JA, Li L, Fukuchi K 2008. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease. J. Neuroinflammation 5:23
    [Google Scholar]
  78. Julier C, Nicolino M. 2010. Wolcott-Rallison syndrome. Orphanet J. Rare Dis. 5:29
    [Google Scholar]
  79. Karran E, Mercken M, De Strooper B 2011. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov. 10:698–712
    [Google Scholar]
  80. Kaushik S, Cuervo AM. 2018. The coming of age of chaperone-mediated autophagy. Nat. Rev. Mol. Cell Biol. 19:365–81
    [Google Scholar]
  81. Khaminets A, Heinrich T, Mari M, Grumati P, Huebner AK et al. 2015. Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 522:354–58
    [Google Scholar]
  82. Kim HJ, Raphael AR, LaDow ES, McGurk L, Weber RA et al. 2014. Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat. Genet. 46:152–60
    [Google Scholar]
  83. Knowles TPJ, Vendruscolo M, Dobson CM 2014. The amyloid state and its association with protein misfolding diseases. Nat. Rev. Mol. Cell Biol. 15:38496
    [Google Scholar]
  84. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J et al. 2006. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–84
    [Google Scholar]
  85. Kwon YT, Ciechanover A. 2017. The ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends Biochem. Sci. 42:873–86
    [Google Scholar]
  86. Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM 2009. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457:1128–32
    [Google Scholar]
  87. Lee B-H, Lee MJ, Park S, Oh D-C, Elsasser S et al. 2010. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467:179–84
    [Google Scholar]
  88. Lee J-E, Sang JC, Rodrigues M, Carr AR, Horrocks MH et al. 2018. Mapping surface hydrophobicity of α-synuclein oligomers at the nanoscale. Nano Lett 18:7494–501
    [Google Scholar]
  89. Lee J-H, Yu WH, Kumar A, Lee S, Mohan PS et al. 2010. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141:1146–58
    [Google Scholar]
  90. Leegwater PA, Vermeulen G, Konst AA, Naidu S, Mulders J et al. 2001. Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat. Genet. 29:383–88
    [Google Scholar]
  91. Leitman J, Hartl FU, Lederkremer GZ 2013. Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress. Nat. Commun. 4:2753
    [Google Scholar]
  92. Li W, Wang X, Van Der Knaap MS, Proud CG 2004. Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways. Mol. Cell. Biol. 24:3295–306
    [Google Scholar]
  93. Li Z, Wang C, Wang Z, Zhu C, Li J et al. 2019. Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. Nature 575:203–9
    [Google Scholar]
  94. Linse S. 2019. Mechanism of amyloid protein aggregation and the role of inhibitors. Pure Appl. Chem. 91:21129
    [Google Scholar]
  95. Liu J, Hoppman N, O'Connell JR, Wang H, Streeten EA et al. 2012. A functional haplotype in EIF2AK3, an ER stress sensor, is associated with lower bone mineral density. J. Bone Miner. Res. 27:331–41
    [Google Scholar]
  96. Lokireddy S, Kukushkin NV, Goldberg AL 2015. cAMP-induced phosphorylation of 26S proteasomes on Rpn6/PSMD11 enhances their activity and the degradation of misfolded proteins. PNAS 112:E717685
    [Google Scholar]
  97. Lopez A, Lee SE, Wojta K, Ramos EM, Klein E et al. 2017. A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction. Brain 140:1128–46
    [Google Scholar]
  98. López-Pérez O, Otero A, Filali H, Sanz-Rubio D, Toivonen JM et al. 2019. Dysregulation of autophagy in the central nervous system of sheep naturally infected with classical scrapie. Sci. Rep. 9:1911
    [Google Scholar]
  99. López-Pérez O, Toivonen JM, Otero A, Solanas L, Zaragoza P et al. 2020. Impairment of autophagy in scrapie-infected transgenic mice at the clinical stage. Lab. Investig. 100:52–63
    [Google Scholar]
  100. Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E et al. 2013. Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits. Nat. Neurosci. 16:1299–305
    [Google Scholar]
  101. Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H et al. 2010. Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nat. Neurosci. 13:567–76
    [Google Scholar]
  102. Meisl G, Knowles TPJ, Klenerman D 2020. The molecular processes underpinning prion-like spreading and seed amplification in protein aggregation. Curr. Opin. Neurobiol. 61:58–64
    [Google Scholar]
  103. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP et al. 2017. Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 93:1015–34
    [Google Scholar]
  104. Mercado G, Castillo V, Soto P, López N, Axten JM et al. 2018. Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of Parkinson's disease. Neurobiol. Dis. 112:136–48
    [Google Scholar]
  105. Michaels TCT, Šarić A, Curk S, Bernfur K, Arosio P et al. 2020. Dynamics of oligomer populations formed during the aggregation of Alzheimer's Aβ42 peptide. Nat. Chem 12:44551
    [Google Scholar]
  106. Miranda AM, Di Paolo G 2018. Endolysosomal dysfunction and exosome secretion: implications for neurodegenerative disorders. Cell Stress 2:115–18
    [Google Scholar]
  107. Moors TE, Paciotti S, Ingrassia A, Quadri M, Breedveld G et al. 2019. Characterization of brain lysosomal activities in GBA-related and sporadic Parkinson's disease and dementia with Lewy bodies. Mol. Neurobiol. 56:1344–55
    [Google Scholar]
  108. Moreno JA, Halliday M, Molloy C, Radford H, Verity N et al. 2013. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci. Transl. Med. 5:206ra138
    [Google Scholar]
  109. Moreno JA, Radford H, Peretti D, Steinert JR, Verity N et al. 2012. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature 485:507–11
    [Google Scholar]
  110. Mudher A, Colin M, Dujardin S, Medina M, Dewachter I et al. 2017. What is the evidence that tau pathology spreads through prion-like propagation. ? Acta Neuropathol. Commun. 5:99
    [Google Scholar]
  111. Mullard A. 2019. Anti-amyloid failures stack up as Alzheimer antibody flops. Nat. Rev. Drug Discov. 18:327
    [Google Scholar]
  112. Myeku N, Clelland CL, Emrani S, Kukushkin NV, Yu WH et al. 2016. Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat. Med. 22:46–53
    [Google Scholar]
  113. Nguyen DKH, Thombre R, Wang J 2019. Autophagy as a common pathway in amyotrophic lateral sclerosis. Neurosci. Lett. 697:34–48
    [Google Scholar]
  114. Nijholt DA, van Haastert ES, Rozemuller AJ, Scheper W, Hoozemans JJ 2012. The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. J. Pathol. 226:693–702
    [Google Scholar]
  115. Novoa I, Zeng H, Harding HP, Ron D 2001. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2α. J. Cell Biol. 153:1011–22
    [Google Scholar]
  116. Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM 2016. The integrated stress response. EMBO Rep 17:1374–95
    [Google Scholar]
  117. Peng C, Trojanowski JQ, Lee VM-Y 2020. Protein transmission in neurodegenerative disease. Nat. Rev. Neurol. 16:199–212
    [Google Scholar]
  118. Pickrell AM, Youle RJ. 2015. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease. Neuron 85:257–73
    [Google Scholar]
  119. Piras A, Collin L, Gruninger F, Graff C, Ronnback A 2016. Autophagic and lysosomal defects in human tauopathies: analysis of post-mortem brain from patients with familial Alzheimer disease, corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol. Commun. 4:22
    [Google Scholar]
  120. Puri C, Manni MM, Vicinanza M, Hilcenko C, Zhu Y et al. 2020. A DNM2 centronuclear myopathy mutation reveals a link between recycling endosome scission and autophagy. Dev. Cell 53:2154–68.e6
    [Google Scholar]
  121. Puri C, Vicinanza M, Ashkenazi A, Gratian MJ, Zhang Q et al. 2018. The RAB11A-positive compartment is a primary platform for autophagosome assembly mediated by WIPI2 recognition of PI3P-RAB11A. Dev. Cell 45:114–31.e8
    [Google Scholar]
  122. Pyo J-O, Yoo S-M, Ahn H-H, Nah J, Hong S-H et al. 2013. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 4:2300
    [Google Scholar]
  123. Radford H, Moreno JA, Verity N, Halliday M, Mallucci GR 2015. PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol 130:633–42
    [Google Scholar]
  124. Ravikumar B, Acevedo-Arozena A, Imarisio S, Berger Z, Vacher C et al. 2005. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat. Genet. 37:771–76
    [Google Scholar]
  125. Ravikumar B, Berger Z, Vacher C, O'Kane CJ, Rubinsztein DC 2006. Rapamycin pre-treatment protects against apoptosis. Hum. Mol. Genet. 15:1209–16
    [Google Scholar]
  126. Ravikumar B, Duden R, Rubinsztein DC 2002. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11:1107–17
    [Google Scholar]
  127. Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE 2009. CD14 and Toll-like receptors 2 and 4 are required for fibrillar Aβ-stimulated microglial activation. J. Neurosci. 29:11982–92
    [Google Scholar]
  128. Remondelli P, Renna M. 2017. The endoplasmic reticulum unfolded protein response in neurodegenerative disorders and its potential therapeutic significance. Front. Mol. Neurosci. 10:187
    [Google Scholar]
  129. Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S et al. 2013. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat. Genet. 45:445–49.e1
    [Google Scholar]
  130. Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ 2001. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. PNAS 98:8554–59
    [Google Scholar]
  131. Sala Frigerio C, De Strooper B 2016. Alzheimer's disease mechanisms and emerging roads to novel therapeutics. Annu. Rev. Neurosci. 39:57–79
    [Google Scholar]
  132. Saxena S, Cabuy E, Caroni P 2009. A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat. Neurosci. 12:627–36
    [Google Scholar]
  133. Schiffmann R, Moller JR, Trapp BD, Shih HH, Farrer RG et al. 1994. Childhood ataxia with diffuse central nervous system hypomyelination. Ann. Neurol. 35:331–40
    [Google Scholar]
  134. Scrivo A, Bourdenx M, Pampliega O, Cuervo AM 2018. Selective autophagy as a potential therapeutic target for neurodegenerative disorders. Lancet Neurol 17:802–15
    [Google Scholar]
  135. Sehgal PB, Westley J, Lerea KM, DiSenso-Browne S, Etlinger JD 2020. Biomolecular condensates in cell biology and virology: phase-separated membraneless organelles (MLOs). Anal. Biochem. 597:113691
    [Google Scholar]
  136. Settembre C, Di Malta C, Polito VA, Garcia-Arencibia M, Vetrini F et al. 2011. TFEB links autophagy to lysosomal biogenesis. Science 332:1429–33
    [Google Scholar]
  137. Settembre C, Fraldi A, Jahreiss L, Spampanato C, Venturi C et al. 2008. A block of autophagy in lysosomal storage disorders. Hum. Mol. Genet. 17:119–29
    [Google Scholar]
  138. Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L et al. 2016. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature 537:50–56
    [Google Scholar]
  139. Shen W-C, Li H-Y, Chen G-C, Chern Y, Tu P-H 2015. Mutations in the ubiquitin-binding domain of OPTN/optineurin interfere with autophagy-mediated degradation of misfolded proteins by a dominant-negative mechanism. Autophagy 11:685–700
    [Google Scholar]
  140. Shoji-Kawata S, Sumpter R, Leveno M, Campbell GR, Zou Z et al. 2013. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494:201–6
    [Google Scholar]
  141. Siddiqi FH, Menzies FM, Lopez A, Stamatakou E, Karabiyik C et al. 2019. Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing. Nat. Commun. 10:1817
    [Google Scholar]
  142. Sidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn BR et al. 2013. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife 2:e00498
    [Google Scholar]
  143. Sidrauski C, McGeachy AM, Ingolia NT, Walter P 2015a. The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. eLife 4:e05033
    [Google Scholar]
  144. Sidrauski C, Tsai JC, Kampmann M, Hearn BR, Vedantham P et al. 2015b. Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response. eLife 4:e07314
    [Google Scholar]
  145. Silva MC, Ferguson FM, Cai Q, Donovan KA, Nandi G et al. 2019. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. eLife 8:e45457
    [Google Scholar]
  146. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S et al. 2003. α-Synuclein locus triplication causes Parkinson's disease. Science 302:841
    [Google Scholar]
  147. Smith HL, Freeman OJ, Butcher AJ, Holmqvist S, Humoud I et al. 2020. Astrocyte unfolded protein response induces a specific reactivity state that causes non-cell-autonomous neuronal degeneration. Neuron 105:855–66.e5
    [Google Scholar]
  148. Soto C, Pritzkow S. 2018. Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat. Neurosci. 21:1332–40
    [Google Scholar]
  149. Spriggs KA, Bushell M, Willis AE 2010. Translational regulation of gene expression during conditions of cell stress. Mol. Cell 40:228–37
    [Google Scholar]
  150. St. George-Hyslop P, Lin JQ, Miyashita A, Phillips EC, Qamar S et al. 2018. The physiological and pathological biophysics of phase separation and gelation of RNA binding proteins in amyotrophic lateral sclerosis and fronto-temporal lobar degeneration. Brain Res 1693:11–23
    [Google Scholar]
  151. Stutzbach LD, Xie SX, Naj AC, Albin R, Gilman S et al. 2013. The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer's disease. Acta Neuropathol. Commun. 1:31
    [Google Scholar]
  152. Sweeney MD, Kisler K, Montagne A, Toga AW, Zlokovic BV 2018. The role of brain vasculature in neurodegenerative disorders. Nat. Neurosci. 21:1318–31
    [Google Scholar]
  153. Tanik SA, Schultheiss CE, Volpicelli-Daley LA, Brunden KR, Lee VM 2013. Lewy body-like α-synuclein aggregates resist degradation and impair macroautophagy. J. Biol. Chem. 288:15194–210
    [Google Scholar]
  154. Taniuchi S, Miyake M, Tsugawa K, Oyadomari M, Oyadomari S 2016. Integrated stress response of vertebrates is regulated by four eIF2α kinases. Sci. Rep. 6:32886
    [Google Scholar]
  155. Teyssou E, Takeda T, Lebon V, Boillee S, Doukoure B et al. 2013. Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology. Acta Neuropathol 125:511–22
    [Google Scholar]
  156. Udan ML, Ajit D, Crouse NR, Nichols MR 2008. Toll-like receptors 2 and 4 mediate Aβ(1–42) activation of the innate immune response in a human monocytic cell line. J. Neurochem. 104:524–33
    [Google Scholar]
  157. van der Knaap MS, Barth PG, Gabreëls FJ, Franzoni E, Begeer JH et al. 1997. A new leukoencephalopathy with vanishing white matter. Neurology 48:845–55
    [Google Scholar]
  158. van der Knaap MS, Leegwater PA, Konst AA, Visser A, Naidu S et al. 2002. Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann. Neurol. 51:264–70
    [Google Scholar]
  159. Vattem KM, Wek RC. 2004. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. PNAS 101:11269–74
    [Google Scholar]
  160. Volpicelli-Daley LA, Gamble KL, Schultheiss CE, Riddle DM, West AB, Lee VM 2014. Formation of α-synuclein Lewy neurite-like aggregates in axons impedes the transport of distinct endosomes. Mol. Biol. Cell 25:4010–23
    [Google Scholar]
  161. Walter P, Ron D. 2011. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–86
    [Google Scholar]
  162. Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC 2003. α-Synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278:25009–13
    [Google Scholar]
  163. Westergard T, McAvoy K, Russell K, Wen X, Pang Y et al. 2019. Repeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation and stress. EMBO Mol. Med. 11:e9423
    [Google Scholar]
  164. Winslow AR, Chen CW, Corrochano S, Acevedo-Arozena A, Gordon DE et al. 2010. α-Synuclein impairs macroautophagy: implications for Parkinson's disease. J. Cell Biol. 190:1023–37
    [Google Scholar]
  165. Wong YC, Holzbaur EL. 2014. The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J. Neurosci. 34:1293–305
    [Google Scholar]
  166. Wong YL, LeBon L, Basso AM, Kohlhaas KL, Nikkel AL et al. 2019. eIF2B activator prevents neurological defects caused by a chronic integrated stress response. eLife 8:e42940
    [Google Scholar]
  167. Wong YL, LeBon L, Edalji R, Lim HB, Sun C, Sidrauski C 2018. The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes. eLife 7:e32733
    [Google Scholar]
  168. Wu X, Fleming A, Ricketts T, Pavel M, Virgin H et al. 2016. Autophagy regulates Notch degradation and modulates stem cell development and neurogenesis. Nat. Commun. 7:10533
    [Google Scholar]
  169. Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD et al. 2005. Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease. J. Cell Biol. 171:87–98
    [Google Scholar]
  170. Zhang J, Lachance V, Schaffner A, Li X, Fedick A et al. 2016. A founder mutation in VPS11 causes an autosomal recessive leukoencephalopathy linked to autophagic defects. PLOS Genet 12:e1005848
    [Google Scholar]
  171. Zhang Y, Zhao Y, Zhang L, Yu W, Wang Y, Chang W 2019. Cellular prion protein as a receptor of toxic amyloid-β42 oligomers is important for Alzheimer's disease. Front. Cell. Neurosci. 13:339
    [Google Scholar]
  172. Zhu PJ, Khatiwada S, Cui Y, Reineke LC, Dooling SW et al. 2019. Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome. Science 366:843–49
    [Google Scholar]
  173. Zhu Y, Runwal G, Obrocki P, Rubinsztein DC 2019. Autophagy in childhood neurological disorders. Dev. Med. Child Neurol. 61:639–45
    [Google Scholar]
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