Abstract
The term proteostasis reflects the fine-tuned balance of cellular protein levels, mediated through a vast network of biochemical pathways. This requires the regulated control of protein folding, post-translational modification, and protein degradation. Due to the complex interactions and intersection of proteostasis pathways, exposure to stress conditions may lead to a disruption of the entire network. Incorrect protein folding and/or modifications during protein synthesis results in inactive or toxic proteins, which may overload degradation mechanisms. Further, a disruption of autophagy and the endoplasmic reticulum degradation pathway may result in additional cellular stress which could ultimately lead to cell death. Neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis all share common risk factors such as oxidative stress, aging, environmental stress, and protein dysfunction; all of which alter cellular proteostasis. The differing pathologies observed in neurodegenerative diseases are determined by factors such as location-specific neuronal death, source of protein dysfunction, and the cell’s ability to counter proteotoxicity. In this review, we discuss how the disruption in cellular proteostasis contributes to the onset and progression of neurodegenerative diseases.
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Coppede F, Migliore L (2015) DNA damage in neurodegenerative diseases. Mutat Res 776:84–97
Hipp MS, Park SH, Hartl FU (2014) Proteostasis impairment in protein-misfolding and -aggregation diseases. Trends Cell Biol 24(9):506–514
Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102
Komatsu M, Ueno T, Waguri S, Uchiyama Y, Kominami E, Tanaka K (2007) Constitutive autophagy: vital role in clearance of unfavorable proteins in neurons. Cell Death Differ 14:887
Tanaka K, Matsuda N (2014) Proteostasis and neurodegeneration: the roles of proteasomal degradation and autophagy. Biochim Biophys Acta 1843(1):197–204
Drazic A, Myklebust LM, Ree R, Arnesen T (2016) The world of protein acetylation. Biochim Biophys Acta 1864(10):1372–1401
Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95(1):55–66
Didonna A, Benetti F (2015) Post-translational modifications in neurodegeneration. AIMS Biophysics 3(1):27–49
Pennuto M, Palazzolo I, Poletti A (2009) Post-translational modifications of expanded polyglutamine proteins: impact on neurotoxicity. Hum Mol Genet 18(R1):R40–R47
Waxman EA, Giasson BI (2011) Characterization of kinases involved in the phosphorylation of aggregated alpha-synuclein. J Neurosci Res 89(2):231–247
Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ, Barbour R, Huang J et al (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281(40):29739–29752
Goncalves S, Outeiro TF (2013) Assessing the subcellular dynamics of alpha-synuclein using photoactivation microscopy. Mol Neurobiol 47(3):1081–1092
Cavallarin N, Vicario M, Negro A (2010) The role of phosphorylation in synucleinopathies: focus on Parkinson’s disease. CNS Neurol Disord Drug Targets 9(4):471–481
Park G, Tan J, Garcia G, Kang Y, Salvesen G, Zhang Z (2016) Regulation of histone acetylation by autophagy in Parkinson disease. J Biol Chem 291(7):3531–3540
Harrison IF, Dexter DT (2013) Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson’s disease? Pharmacol Ther 140(1):34–52
Wilkinson KD (1987) Protein ubiquitination: a regulatory post-translational modification. Anticancer Drug Des 2(2):211–229
Pickart CM (1997) Targeting of substrates to the 26S proteasome. FASEB J 11(13):1055–1066
Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, Banerjee S, Youle RJ (2014) PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol 205(2):143–153
Kazlauskaite A, Martinez-Torres RJ, Wilkie S, Kumar A, Peltier J, Gonzalez A, Johnson C, Zhang J et al (2015) Binding to serine 65-phosphorylated ubiquitin primes Parkin for optimal PINK1-dependent phosphorylation and activation. EMBO Rep 16(8):939–954
Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, Pletnikova O, Troncoso JC et al (2010) Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function. Proc Natl Acad Sci U S A 107(38):16691–16696
Song P, Li S, Wu H, Gao R, Rao G, Wang D, Chen Z, Ma B et al (2016) Parkin promotes proteasomal degradation of p62: implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson’s disease. Protein Cell 7(2):114–129
Vicente Miranda H, Cássio R, Correia-Guedes L, Gomes MA, Chegão A, Miranda E, Soares T, Coelho M et al (2017) Posttranslational modifications of blood-derived alpha-synuclein as biochemical markers for Parkinson’s disease. Sci Rep 7(1):13713
Krumova P, Meulmeester E, Garrido M, Tirard M, Hsiao HH, Bossis G, Urlaub H, Zweckstetter M et al (2011) Sumoylation inhibits alpha-synuclein aggregation and toxicity. J Cell Biol 194(1):49–60
Almos PZ, Horváth S, Czibula A, Raskó I, Sipos B, Bihari P, Béres J, Juhász A et al (2008) H1 tau haplotype-related genomic variation at 17q21.3 as an Asian heritage of the European Gypsy population. Heredity (Edinb) 101(5):416–419
Zhang Y, Tian Q, Zhang Q, Zhou X, Liu S, Wang JZ (2009) Hyperphosphorylation of microtubule-associated tau protein plays dual role in neurodegeneration and neuroprotection. Pathophysiology 16(4):311–316
Serenó L, Coma M, Rodríguez M, Sánchez-Ferrer P, Sánchez MB, Gich I, Agulló JM, Pérez M et al (2009) A novel GSK-3beta inhibitor reduces Alzheimer’s pathology and rescues neuronal loss in vivo. Neurobiol Dis 35(3):359–367
Tanimukai H, Grundke-Iqbal I, Iqbal K (2005) Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer’s disease. Am J Pathol 166(6):1761–1771
Gong CX, Lidsky T, Wegiel J, Zuck L, Grundke-Iqbal I, Iqbal K (2000) Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer’s disease. J Biol Chem 275(8):5535–5544
Kaneko M, Koike H, Saito R, Kitamura Y, Okuma Y, Nomura Y (2010) Loss of HRD1-mediated protein degradation causes amyloid precursor protein accumulation and amyloid-beta generation. J Neurosci 30(11):3924–3932
Thinakaran G, Koo EH (2008) Amyloid precursor protein trafficking, processing, and function. J Biol Chem 283(44):29615–29619
Llorens-Martín M, Jurado J, Hernández F, Avila J (2014) GSK-3beta, a pivotal kinase in Alzheimer disease. Front Mol Neurosci 7:46
Feligioni M, Brambilla E, Camassa A, Sclip A, Arnaboldi A, Morelli F, Antoniou X, Borsello T (2011) Crosstalk between JNK and SUMO signaling pathways: deSUMOylation is protective against H2O2-induced cell injury. PLoS One 6(12):e28185
Lee MR, Lee D, Shin SK, Kim YH, Choi CY (2008) Inhibition of APP intracellular domain (AICD) transcriptional activity via covalent conjugation with Nedd8. Biochem Biophys Res Commun 366(4):976–981
Gong L, Yeh ET (1999) Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway. J Biol Chem 274(17):12036–12042
Chen Y, Bodles AM, McPhie DL, Neve RL, Mrak RE, Griffin WST (2007) APP-BP1 inhibits Abeta42 levels by interacting with Presenilin-1. Mol Neurodegener 2:3
Laifenfeld D, Patzek LJ, McPhie DL, Chen Y, Levites Y, Cataldo AM, Neve RL (2007) Rab5 mediates an amyloid precursor protein signaling pathway that leads to apoptosis. J Neurosci 27(27):7141–7153
Del Prete D, Checler F, Chami M (2014) Ryanodine receptors: physiological function and deregulation in Alzheimer disease. Mol Neurodegener 9:21
Liu X, Betzenhauser MJ, Reiken S, Meli AC, Xie W, Chen BX, Arancio O, Marks AR (2012) Role of leaky neuronal ryanodine receptors in stress-induced cognitive dysfunction. Cell 150(5):1055–1067
Bussiere R, Lacampagne A, Reiken S, Liu X, Scheuerman V, Zalk R, Martin C, Checler F et al (2017) Amyloid beta production is regulated by beta2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor. J Biol Chem 292(24):10153–10168
Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362(6415):59–62
Fei E, Jia N, Yan M, Ying Z, Sun Q, Wang H, Zhang T, Ma X et al (2006) SUMO-1 modification increases human SOD1 stability and aggregation. Biochem Biophys Res Commun 347(2):406–412
Gibb SL, Boston-Howes W, Lavina ZS, Gustincich S, Brown RH Jr, Pasinelli P, Trotti D (2007) A caspase-3-cleaved fragment of the glial glutamate transporter EAAT2 is sumoylated and targeted to promyelocytic leukemia nuclear bodies in mutant SOD1-linked amyotrophic lateral sclerosis. J Biol Chem 282(44):32480–32490
Kaliszewski M, Kennedy AK, Blaes SL, Shaffer RS, Knott AB, Song W, Hauser HA, Bossy B et al (2016) SOD1 lysine 123 acetylation in the adult central nervous system. Front Cell Neurosci 10:287
Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F et al (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477(7363):211–215
Chang L, Monteiro MJ (2015) Defective proteasome delivery of polyubiquitinated proteins by ubiquilin-2 proteins containing ALS mutations. PLoS One 10(6):e0130162
Rakhit R, Cunningham P, Furtos-Matei A, Dahan S, Qi XF, Crow JP, Cashman NR, Kondejewski LH et al (2002) Oxidation-induced misfolding and aggregation of superoxide dismutase and its implications for amyotrophic lateral sclerosis. J Biol Chem 277(49):47551–47556
Mishra A, Maheshwari M, Chhangani D, Fujimori-Tonou N, Endo F, Joshi AP, Jana NR, Yamanaka K (2013) E6-AP association promotes SOD1 aggresomes degradation and suppresses toxicity. Neurobiol Aging 34(4):1310 e11–1310 e23
Pardo CA, Xu Z, Borchelt DR, Price DL, Sisodia SS, Cleveland DW (1995) Superoxide dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons. Proc Natl Acad Sci U S A 92(4):954–958
Niikura T, Kita Y, Abe Y (2014) SUMO3 modification accelerates the aggregation of ALS-linked SOD1 mutants. PLoS One 9(6):e101080
Nakamura T, Cho DH, Lipton SA (2012) Redox regulation of protein misfolding, mitochondrial dysfunction, synaptic damage, and cell death in neurodegenerative diseases. Exp Neurol 238(1):12–21
Bristol LA, Rothstein JD (1996) Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex. Ann Neurol 39(5):676–679
Foran E, Rosenblum L, Bogush A, Pasinelli P, Trotti D (2014) Sumoylation of the astroglial glutamate transporter EAAT2 governs its intracellular compartmentalization. Glia 62(8):1241–1253
Sharma A, Lyashchenko AK, Lu L, Nasrabady SE, Elmaleh M, Mendelsohn M, Nemes A, Tapia JC et al (2016) ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat Commun 7:10465
Renton AE, Chio A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17(1):17–23
Mastrocola AS, Kim SH, Trinh AT, Rodenkirch LA, Tibbetts RS (2013) The RNA-binding protein fused in sarcoma (FUS) functions downstream of poly(ADP-ribose) polymerase (PARP) in response to DNA damage. J Biol Chem 288(34):24731–24741
Cheng IH, Scearce-Levie K, Legleiter J, Palop JJ, Gerstein H, Bien-Ly N, Puoliväli J, Lesné S et al (2007) Accelerating amyloid-β fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem 282(33):23818–23828
Winklhofer KF, Tatzelt J, Haass C (2008) The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases. EMBO J 27(2):336–349
Helwig M, Klinkenberg M, Rusconi R, Musgrove RE, Majbour NK, el-Agnaf OMA, Ulusoy A, di Monte DA (2016) Brain propagation of transduced alpha-synuclein involves non-fibrillar protein species and is enhanced in alpha-synuclein null mice. Brain 139(Pt 3):856–870
Luk KC, Song C, O'Brien P, Stieber A, Branch JR, Brunden KR, Trojanowski JQ, Lee VMY (2009) Exogenous α-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci 106(47):20051–20056
Abdullah R, Patil KS, Rosen B, Pal R, Prabhudesai S, Lee S, Basak I, Hoedt E et al (2017) Subcellular Parkinson’s disease-specific alpha-synuclein species show altered behavior in neurodegeneration. Mol Neurobiol 54(10):7639–7655
Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, Hetzer C, Loher T et al (2011) In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci U S A 108(10):4194–4199
Prots I, Veber V, Brey S, Campioni S, Buder K, Riek R, Böhm KJ, Winner B (2013) alpha-Synuclein oligomers impair neuronal microtubule-kinesin interplay. J Biol Chem 288(30):21742–21754
Emamzadeh FN (2016) Alpha-synuclein structure, functions, and interactions. J Res Med Sci 21:29
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I et al (1998) Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci 95(11):6448–6453
Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-[beta] protein assembly in the brain impairs memory. Nature 440(7082):352–357
Leroy K, Ando K, Laporte V, Dedecker R, Suain V, Authelet M, Héraud C, Pierrot N et al (2012) Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1 mice. Am J Pathol 181(6):1928–1940
Kopeikina KJ, Hyman BT, Spires-Jones TL (2012) Soluble forms of tau are toxic in Alzheimer’s disease. Transl Neurosci 3(3):223–233
Kanaan NM, Pigino GF, Brady ST, Lazarov O, Binder LI, Morfini GA (2013) Axonal degeneration in Alzheimer’s disease: when signaling abnormalities meet the axonal transport system. Exp Neurol 246:44–53
Yuan A, Kumar A, Peterhoff C, Duff K, Nixon RA (2008) Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice. J Neurosci 28(7):1682–7
Arrasate M, Finkbeiner S (2012) Protein aggregates in Huntington’s disease. Exp Neurol 238(1):1–11
Miller J, Arrasate M, Shaby BA, Mitra S, Masliah E, Finkbeiner S (2010) Quantitative relationships between huntingtin levels, polyglutamine length, inclusion body formation, and neuronal death provide novel insight into Huntington’s disease molecular pathogenesis. J Neurosci 30(31):10541–10550
Saudou F, Humbert S (2016) The biology of huntingtin. Neuron 89(5):910–926
Harper SQ, Staber PD, He X, Eliason SL, Martins IH, Mao Q, Yang L, Kotin RM et al (2005) RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc Natl Acad Sci U S A 102(16):5820–5825
O'Kusky JR, Nasir J, Cicchetti F, Parent A, Hayden MR (1999) Neuronal degeneration in the basal ganglia and loss of pallido-subthalamic synapses in mice with targeted disruption of the Huntington’s disease gene. Brain Res 818(2):468–479
Westergard T, Jensen BK, Wen X, Cai J, Kropf E, Iacovitti L, Pasinelli P, Trotti D (2016) Cell-to-cell transmission of dipeptide repeat proteins linked to C9orf72-ALS/FTD. Cell Rep 17(3):645–652
Robinson JL, Geser F, Stieber A, Umoh M, Kwong LK, van Deerlin VM, Lee VMY, Trojanowski JQ (2013) TDP-43 skeins show properties of amyloid in a subset of ALS cases. Acta Neuropathol 125(1):121–131
Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Velde CV, Bouchard JP, Lacomblez L et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574
Chan PK, Chattopadhyay M, Sharma S, Souda P, Gralla EB, Borchelt DR, Whitelegge JP, Valentine JS (2013) Structural similarity of wild-type and ALS-mutant superoxide dismutase-1 fibrils using limited proteolysis and atomic force microscopy. Proc Natl Acad Sci 110(27):10934–10939
Pedrini S, Sau D, Guareschi S, Bogush M, Brown RH Jr, Naniche N, Kia A, Trotti D et al (2010) ALS-linked mutant SOD1 damages mitochondria by promoting conformational changes in Bcl-2. Hum Mol Genet 19(15):2974–2986
Sau D, de Biasi S, Vitellaro-Zuccarello L, Riso P, Guarnieri S, Porrini M, Simeoni S, Crippa V et al (2007) Mutation of SOD1 in ALS: a gain of a loss of function. Hum Mol Genet 16(13):1604–1618
Serio TR, Cashikar AG, Kowal AS, Sawicki GJ, Moslehi JJ, Serpell L, Arnsdorf MF, Lindquist SL (2000) Nucleated conformational conversion and the replication of conformational information by a prion determinant. Science 289(5483):1317–1321
Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, Hein MY, Stoynov S, Mahamid J et al (2015) A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162(5):1066–1077
Brangwynne CP, Tompa P, Pappu RV (2015) Polymer physics of intracellular phase transitions. Nat Phys 11:899–904
Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP, Kim HJ, Mittag T, Taylor JP (2015) Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163(1):123–133
Iurlaro R, Munoz-Pinedo C (2016) Cell death induced by endoplasmic reticulum stress. FEBS J 283(14):2640–2652
Colla E, Jensen PH, Pletnikova O, Troncoso JC, Glabe C, Lee MK (2012) Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo. J Neurosci 32(10):3301–3305
Credle JJ, Forcelli PA, Delannoy M, Oaks AW, Permaul E, Berry DL, Duka V, Wills J et al (2015) alpha-Synuclein-mediated inhibition of ATF6 processing into COPII vesicles disrupts UPR signaling in Parkinson’s disease. Neurobiol Dis 76:112–125
Omura T, Kaneko M, Okuma Y, Matsubara K, Nomura Y (2013) Endoplasmic reticulum stress and Parkinson’s disease: the role of HRD1 in averting apoptosis in neurodegenerative disease. Oxidative Med Cell Longev 2013:239854
Ryu EJ, Harding HP, Angelastro JM, Vitolo OV, Ron D, Greene LA (2002) Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson’s disease. J Neurosci 22(24):10690–10698
Hetz C, Chevet E, Harding HP (2013) Targeting the unfolded protein response in disease. Nat Rev Drug Discov 12:703–719
Chano T, Okabe H, Hulette CM (2007) RB1CC1 insufficiency causes neuronal atrophy through mTOR signaling alteration and involved in the pathology of Alzheimer’s diseases. Brain Res 1168:97–105
Yoon SO, Park DJ, Ryu JC, Ozer HG, Tep C, Shin YJ, Lim TH, Pastorino L et al (2012) JNK3 perpetuates metabolic stress induced by Abeta peptides. Neuron 75(5):824–837
Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C, Lennon CJ, Kluger Y et al (2007) XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol Cell 27(1):53–66
O'Connor T, Sadleir KR, Maus E, Velliquette RA, Zhao J, Cole SL, Eimer WA, Hitt B et al (2008) Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron 60(6):988–1009
Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E, Pierre P, Cavener DR, Klann E (2013) Suppression of eIF2alpha kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nat Neurosci 16(9):1299–1305
Carnemolla A, Fossale E, Agostoni E, Michelazzi S, Calligaris R, de Maso L, del Sal G, MacDonald ME et al (2009) Rrs1 is involved in endoplasmic reticulum stress response in Huntington disease. J Biol Chem 284(27):18167–18173
Duennwald ML, Lindquist S (2008) Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity. Genes Dev 22(23):3308–3319
Yang D, Wang CE, Zhao B, Li W, Ouyang Z, Liu Z, Yang H, Fan P et al (2010) Expression of Huntington’s disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum Mol Genet 19(20):3983–3994
Lajoie P, Snapp EL (2011) Changes in BiP availability reveal hypersensitivity to acute endoplasmic reticulum stress in cells expressing mutant huntingtin. J Cell Sci 124(Pt 19):3332–3343
Wang CE, Tydlacka S, Orr AL, Yang SH, Graham RK, Hayden MR, Li S, Chan AWS et al (2008) Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington's disease. Hum Mol Genet 17(17):2738–2751
Wang J, Wang CE, Orr A, Tydlacka S, Li SH, Li XJ (2008) Impaired ubiquitin-proteasome system activity in the synapses of Huntington’s disease mice. J Cell Biol 180(6):1177–1189
Jiang Y, Chadwick SR, Lajoie P (2016) Endoplasmic reticulum stress: the cause and solution to Huntington's disease? Brain Res 1648:650–657
Hetz C, Mollereau B (2014) Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci 15(4):233–249
Hetz C, Russelakis-Carneiro M, Maundrell K, Castilla J, Soto C (2003) Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J 22(20):5435–5445
Xu K, Zhu XP (2012) Endoplasmic reticulum stress and prion diseases. Rev Neurosci 23(1):79–84
Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE et al (2013) Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 5(206):206ra138
Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J et al (2012) Sustained translational repression by eIF2α–P mediates prion neurodegeneration. Nature 485(7399):507–511
Menzies FM, Moreau K, Rubinsztein DC (2011) Protein misfolding disorders and macroautophagy. Curr Opin Cell Biol 23(2):190–197
Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451(7182):1069–1075
Lum JJ, DeBerardinis RJ, Thompson CB (2005) Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 6(6):439–448
Wong E, Cuervo AM (2010) Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 13(7):805–811
Sarkar S (2013) Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. Biochem Soc Trans 41(5):1103–1130
Vidal RL, Matus S, Bargsted L, Hetz C (2014) Targeting autophagy in neurodegenerative diseases. Trends Pharmacol Sci 35(11):583–591
Marino G, Madeo F, Kroemer G (2011) Autophagy for tissue homeostasis and neuroprotection. Curr Opin Cell Biol 23(2):198–206
Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, Meier F, Ozmen L, Bluethmann H et al (2009) Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci U S A 106(47):20057–20062
Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, Metivier D, Meley D et al (2005) Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol 25(3):1025–1040
Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M et al (2005) Macroautophagy—a novel Beta-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol 171(1):87–98
Coffey EE, Beckel JM, Laties AM, Mitchell CH (2014) Lysosomal alkalization and dysfunction in human fibroblasts with the Alzheimer’s disease-linked presenilin 1 A246E mutation can be reversed with cAMP. Neuroscience 263:111–124
Mindell JA (2012) Lysosomal acidification mechanisms. Annu Rev Physiol 74:69–86
Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M et al (2010) Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141(7):1146–1158
Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305(5688):1292–1295
Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A 105(5):1638–1643
Krebiehl G, Ruckerbauer S, Burbulla LF, Kieper N, Maurer B, Waak J, Wolburg H, Gizatullina Z et al (2010) Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson’s disease-associated protein DJ-1. PLoS One 5(2):e9367
Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183(5):795–803
Pickrell AM, Fukui H, Wang X, Pinto M, Moraes CT (2011) The striatum is highly susceptible to mitochondrial oxidative phosphorylation dysfunctions. J Neurosci 31(27):9895–9904
Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S, de Vries R, Arias E et al (2010) Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci 13(5):567–576
Liang Q, Ouyang X, Schneider L, Zhang J (2011) Reduction of mutant huntingtin accumulation and toxicity by lysosomal cathepsins D and B in neurons. Mol Neurodegener 6:37
Wang P, Li B, Zhou L, Fei E, Wang G (2011) The KDEL receptor induces autophagy to promote the clearance of neurodegenerative disease-related proteins. Neuroscience 190:43–55
Pasinelli P, Brown RH (2006) Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci 7(9):710–723
Sasaki S (2011) Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 70(5):349–359
Johnson JO, Mandrioli J, Benatar M, Abramzon Y, van Deerlin VM, Trojanowski JQ, Gibbs JR, Brunetti M et al (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68(5):857–864
Crippa V, Sau D, Rusmini P, Boncoraglio A, Onesto E, Bolzoni E, Galbiati M, Fontana E et al (2010) The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS). Hum Mol Genet 19(17):3440–3456
Gomes C, Escrevente C, Costa J (2010) Mutant superoxide dismutase 1 overexpression in NSC-34 cells: effect of trehalose on aggregation, TDP-43 localization and levels of co-expressed glycoproteins. Neurosci Lett 475(3):145–149
Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA et al (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 26(13):3169–3179
Abdullah R, Basak I, Patil KS, Alves G, Larsen JP, Møller SG (2014) Parkinson's disease and age: the obvious but largely unexplored link. Exp Gerontol 68:33–38
Johri A, Beal MF (2012) Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther:619–630
Kawamoto Y, Kobayashi Y, Suzuki Y, Inoue H, Tomimoto H, Akiguchi I, Budka H, Martins LM et al (2008) Accumulation of HtrA2/Omi in neuronal and glial inclusions in brains with alpha-synucleinopathies. J Neuropathol Exp Neurol 67(10):984–993
Moisoi N, Klupsch K, Fedele V, East P, Sharma S, Renton A, Plun-Favreau H, Edwards RE et al (2009) Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response. Cell Death Differ 16(3):449–464
Thomas KJ, McCoy MK, Blackinton J, Beilina A, van der Brug M, Sandebring A, Miller D, Maric D et al (2011) DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. Hum Mol Genet 20(1):40–50
Siddiqui A, Chinta SJ, Mallajosyula JK, Rajagopolan S, Hanson I, Rane A, Melov S, Andersen JK (2012) Selective binding of nuclear alpha-synuclein to the PGC1alpha promoter under conditions of oxidative stress may contribute to losses in mitochondrial function: implications for Parkinson’s disease. Free Radic Biol Med 53(4):993–1003
Swerdlow RH, Burns JM, Khan SM (2010) The Alzheimer’s disease mitochondrial cascade hypothesis. J Alzheimers Dis 20(Suppl 2):S265–S279
Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58(4):495–505
Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA, Murri L, Rapoport SI et al (2002) Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease. Neurobiol Aging 23(3):371–376
Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X (2008) Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A:19318–19323
Munguia ME, Govezensky T, Martinez R, Manoutcharian K, Gevorkian G (2006) Identification of amyloid-beta 1–42 binding protein fragments by screening of a human brain cDNA library. Neurosci Lett 397(1):79–82
Ono K, Hamaguchi T, Naiki H, Yamada M (2006) Anti-amyloidogenic effects of antioxidants: implications for the prevention and therapeutics of Alzheimer’s disease. Biochim Biophys Acta (BBA) - Mol Basis Dis 1762(6):575–586
Jiang D, Li X, Williams R, Patel S, Men L, Wang Y, Zhou F (2009) Ternary complexes of iron, amyloid-beta, and nitrilotriacetic acid: binding affinities, redox properties, and relevance to iron-induced oxidative stress in Alzheimer’s disease. Biochemistry 48(33):7939–7947
Misonou H, Morishima-Kawashima M, Ihara Y (2000) Oxidative stress induces intracellular accumulation of amyloid beta-protein (Abeta) in human neuroblastoma cells. Biochemistry 39(23):6951–6959
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Research in our laboratory is funded by The Norwegian Center for Movement Disorders, The Norwegian Parkinson’s Foundation, and St. John’s University.
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Kurtishi, A., Rosen, B., Patil, K.S. et al. Cellular Proteostasis in Neurodegeneration. Mol Neurobiol 56, 3676–3689 (2019). https://doi.org/10.1007/s12035-018-1334-z
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DOI: https://doi.org/10.1007/s12035-018-1334-z