Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies

Experimental and Molecular Medicine

Volumn 47, Issue 3, 2015, Pages

  Ciechanover, Aaron ^a,b   Kwon, Yong Tae ^a  

^a Seoul National University College of Medicine   (South Korea)

^b TECHNION ISRAEL INSTITUTE OF TECHNOLOGY   (Israel)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA SYNUCLEIN; AMYLOID BETA PROTEIN; DNA BINDING PROTEIN; HTT PROTEIN, HUMAN; NERVE PROTEIN; PRION PROTEIN; PROTEASOME; PROTEIN TDP-43; SUPEROXIDE DISMUTASE; TAU PROTEIN; UBIQUITIN;

ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; ANIMAL; AUTOPHAGY; DRUG EFFECTS; GENETICS; HUMAN; HUNTINGTON DISEASE; LYSOSOME; METABOLISM; MOLECULARLY TARGETED THERAPY; MUTATION; NEURODEGENERATIVE DISEASES; PARKINSON DISEASE; PRION DISEASES; PROTEIN DEGRADATION; PROTEOSTASIS DEFICIENCY;

ALPHA-SYNUCLEIN; ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; AMYOTROPHIC LATERAL SCLEROSIS; ANIMALS; AUTOPHAGY; DNA-BINDING PROTEINS; HUMANS; HUNTINGTON DISEASE; LYSOSOMES; MOLECULAR TARGETED THERAPY; MUTATION; NERVE TISSUE PROTEINS; NEURODEGENERATIVE DISEASES; PARKINSON DISEASE; PRION DISEASES; PROTEASOME ENDOPEPTIDASE COMPLEX; PROTEOLYSIS; PROTEOSTASIS DEFICIENCIES; PRPSC PROTEINS; SUPEROXIDE DISMUTASE; TAU PROTEINS; UBIQUITIN;

EID: 84989284335     PISSN: 12263613     EISSN: 20926413     Source Type: Journal    
DOI: 10.1038/EMM.2014.117     Document Type: Review

References (228)

1. Ciechanover A. Intracellular protein degradation: from a vague idea through the lysosome and the ubiquitin–proteasome system and onto human diseases and drug targeting. Bioorg Med Chem 2013; 21: 3400–3410.
2. Sriram SM, Kim BY, Kwon YT. The N-end rule pathway: emerging functions and molecular principles of substrate recognition. Nat Rev Mol Cell Biol 2011; 12: 735–747.
3. Tasaki T, Sriram SM, Park KS, Kwon YT. The N-end rule pathway. Annu Rev Biochem 2012; 81: 261–289.
4. Kim ST, Tasaki T, Zakrzewska A, Yoo YD, Sung KS, Kim BY et al. The N-end rule proteolytic system in autophagy. Autophagy 2013; 9: 1100–1103.
5. Rothenberg C, Srinivasan D, Mah L, Kaushik S, Peterhoff CM, Ugolino J et al. Ubiquilin functions in autophagy and is degraded by chaper-one-mediated autophagy. Hum Mol Genet 2010; 19: 3219–3232.
6. Kiffin R, Christian C, Knecht E, Cuervo AM. Activation of chaperone-mediated autophagy during oxidative stress. Mol Biol Cell 2004; 15: 4829–4840.
7. Hariharan N, Zhai P, Sadoshima J. Oxidative stress stimulates autophagic flux during ischemia/reperfusion. Antioxid Redox Signal 2011; 14: 2179–2190.
8. Koga H, Cuervo AM. Chaperone-mediated autophagy dysfunction in the pathogenesis of neurodegeneration. Neurobiol Dis 2011; 43: 29–37.
9. Kopito RR. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 2000; 10: 524–530.
10. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002; 19: 353–356.
11. Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell 2012; 148: 1204–1222.
12. Ward SM, Himmelstein DS, Lancia JK, Binder LI. Tau oligomers and tau toxicity in neurodegenerative disease. Biochem Soc Trans 2012; 40: 667–671.
13. Williams A, Sarkar S, Cuddon P, Ttofi EK, Saiki S, Siddiqi FH et al. Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nat Chem Biol 2008; 4: 295–305.
14. Tsoi H, Lau TC, Tsang SY, Lau KF, Chan HY. CAG expansion induces nucleolar stress in polyglutamine diseases. Proc Natl Acad Sci USA 2012; 109: 13428–13433.
15. Martin I, Dawson VL, Dawson TM. Recent advances in the genetics of Parkinson’s disease. Annu Rev Genomics Hum Genet 2011; 12: 301–325.
16. Uversky VN. Neuropathology, biochemistry, and biophysics of α-synuclein aggregation. J Neurochem 2007; 103: 17–37.
17. Griffith JS. Self-replication and scrapie. Nature 1967; 215: 1043–1044.
18. Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982; 216: 136–144.
19. Prusiner SB. Prions. Proc Natl Acad Sci USA 1998; 95: 13363–13383.
20. Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nature Rev Neurol 2011; 7: 603–615.
21. Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem 2005; 280: 17294–17300.
22. Lee S, Sato Y, Nixon RA. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer’s-like axonal dystrophy. JNeurosci2011; 31: 7817–7830.
23. Hollenbeck PJ. Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport. JCellBiol1993; 121: 305–315.
24. Larsen KE, Sulzer D. Autophagy in neurons: a review. Histol Histopathol 2002; 17: 897–908.
25. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006; 441: 885–889.
26. Mizushima N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 2010; 22: 132–139.
27. Keller JN, Huang FF, Markesbery WR. Decreased levels of proteasome activity and proteasome expression in aging spinal cord. Neuroscience 2000; 98: 149–156.
28. Jung KM, Astarita G, Zhu C, Wallace M, Mackie K, Piomelli D. A key role for diacylglycerol lipase-alpha in metabotropic glutamate receptor-dependent endocannabinoid mobilization. Mol Pharmacol 2007; 72: 612–621.
29. Tydlacka S, Wang CE, Wang X, Li S, Li XJ. Differential activities of the ubiquitin-proteasome system in neurons versus glia may account for the preferential accumulation of misfolded proteins in neurons. JNeurosci2008; 28: 13285–13295.
30. Dantuma NP, Lindsten K. Stressing the ubiquitin-proteasome system. Cardiovascular Research 2010; 85: 263–271.
31. Löw K, Aebischer P. Use of viral vectors to create animal models for Parkinson's disease. Neurobiol Dis 2012; 48: 189–201.
32. Tai HC, Serrano-Pozo A, Hashimoto T, Frosch MP, Spires-Jones TL, Hyman BT. The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am J Pathol 2012; 181: 1426–1435.
33. Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC. Alpha-synuclein is degraded by both autophagy and the proteasome. JBiolChem2003; 278: 25009–25013.
34. Sarkar S, Krishna G, Imarisio S, Saiki S, O'Kane CJ, Rubinsztein DC. A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum Mol Genet 2008; 17: 170–178.
35. Heiseke A, Aguib Y, Riemer C, Baier M, Schätzl HM. Lithium induces clearance of protease resistant prion protein in prion-infected cells by induction of autophagy. JNeurochem2009; 109: 25–34.
36. Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem 2010; 285: 13107–13120.
37. Rodriguez-Navarro JA, Cuervo AM. Autophagy and lipids: tightening the knot. Semin Immunopathol 2010; 32: 343–353.
38. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer’s disease. PLoS ONE 2010; 5: e9979.
39. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem 1998; 67: 425–479.
40. Qian SB, McDonough H, Boellmann F, Cyr DM, Patterson C. CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70. Nature 2006; 440: 551–555.
41. Peng J, Schwartz D, Elias JE, Thoreen CC, Cheng D, Marsischky G et al. A proteomics approach to understanding protein ubiquitination. Nat Biotechnol 2003; 21: 921–926.
42. Hadian K, Griesbach RA, Dornauer S, Wanger TM, Nagel D, Metlitzky M et al. NF-kappaB essential modulator (NEMO) interaction with linear and lys-63 ubiquitin chains contributes to NF-kappaB activation. JBiolChem 2011; 286: 26107–26117.
43. Matsumoto ML, Wickliffe KE, Dong KC, Yu C, Bosanac I, Bustos D et al. K11-linked polyubiquitination in cell cycle control revealed by a K11 linkage-specific antibody. Mol Cell 2010; 39: 477–484.
44. Sowa ME, Bennett EJ, Gygi SP, Harper JW. Defining the human deubiquitinating enzyme interaction landscape. Cell 2009; 138: 389–403.
45. Komander D, Rape M. The ubiquitin code. Annu Rev Biochem 2012; 81: 203–229.
46. Clague MJ, Urbé S. Ubiquitin: same molecule, different degradation pathways. Cell 2010; 143: 682–685.
47. Hendil KB, Khan S, Tanaka K. Simultaneous binding of PA28 and PA700 activators to 20 S proteasomes. Biochem J 1998; 332: 749–754.
48. Tanahashi N, Murakami Y, Minami Y, Shimbara N, Hendil KB, Tanaka K. Hybrid proteasomes. Induction by interferon-gamma and contribution to ATP-dependent proteolysis. JBiolChem2000; 275: 14336–14345.
49. Ravid T, Hochstrasser M. Diversity of degradation signals in the ubiquitin–proteasome system. Nat Rev Mol Cell Biol 2008; 9: 679–690.
50. Eisele F, Wolf DH. Degradation of misfolded protein in the cytoplasm is mediated by the ubiquitin ligase Ubr1. FEBS Lett 2008; 582: 4143–4146.
51. Heck JW, Cheung SK, Hampton RY. Cytoplasmic protein quality control degradation mediated by parallel actions of the E3 ubiquitin ligases Ubr1 and San1. Proc Natl Acad Sci USA 2010; 107: 1106–1111.
52. Fredrickson EK, Rosenbaum JC, Locke MN, Milac TI, Gardner RG. Exposed hydrophobicity is a key determinant of nuclear quality control degradation. Mol Biol Cell 2011; 22: 2384–2395.
53. Prasad R, Kawaguchi S, Ng DT. A nucleus-based quality control mechanism for cytosolic proteins. Mol Biol Cell 2010; 21: 2117–2127.
54. Fang NN, Ng AH, Measday V, Mayor T. Hul5 HECT ubiquitin ligase plays a major role in the ubiquitylation and turnover of cytosolic misfolded proteins. Nat Cell Biol 2011; 13: 1344–1352.
55. Connell CM, Shaw BA, Holmes SB, Foster NL. Caregivers' attitudes toward their family members' participation in Alzheimer disease research: implications for recruitment and retention. Alzheimer Dis Assoc Disord 2001; 15: 137–145.
56. Hegde AN, Upadhya SC. Role of ubiquitin-proteasome mediated proteolysis in nervous system disease. Biochim Biophys Acta 2011; 1809: 128–140.
57. Dennissen FJ, Kholod N, van Leeuwen FW. The ubiquitin proteasome system in neurodegenerative diseases: culprit, accomplice or victim? Prog Neurobiol 2012; 96: 190–207.
58. Andre R, Tabrizi SJ. Misfolded PrP and a novel mechanism of proteasome inhibition. Prion 2012; 6: 32–36.
59. Gregori L, Fuchs C, Figueiredo-Pereira ME, Van Nostrand WE, Goldgaber D. Amyloid-protein inhibits ubiquitin-dependent protein degradation in vitro. JBiolChem1995; 270: 19702–19708.
60. Snyder H, Mensah K, Theisler C, Lee J, Matouschek A, Wolozin B. Aggregated and monomeric α-synuclein bind to the S6’ proteasomal protein and inhibit proteasomal function. J Biol Chem 2003; 278: 11753–11759.
61. Lindersson E, Beedholm R, Højrup P, Moos T, Gai W, Hendil KB et al. Proteasomal inhibition by alpha-synuclein filaments and oligomers. JBiol Chem 2004; 279: 12924–12934.
62. Kristiansen M, Deriziotis P, Dimcheff DE, Jackson GS, Ovaa H, Naumann H et al. Disease-associated prion protein oligomers inhibit the 26S proteasome. Mol Cell 2007; 26: 175–188.
63. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimerrelated PS1 mutations. Cell 2010; 141: 1146–1158.
64. Nixon RA, Yang DS, Lee JH. Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy 2008; 4: 590–599.
65. Kaushik S, Cuervo AM. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol 2012; 22: 407–417.
66. Kaushik S, Massey AC, Mizushima N, Cuervo AM. Constitutive activation of chaperone-mediated autophagy in cells with impaired macroautophagy. Mol Biol Cell 2008; 19: 2179–2192.
67. Deretic V. Autophagy in infection. Curr Opin Cell Biol 2010; 22: 252–262.
68. Ichimura Y, Kominami E, Tanaka K, Komatsu M. Selective turnover of p62/A170/SQSTM1 by autophagy. Autophagy 2008; 4: 1063–1066.
69. Ichimura Y, Kumanomidou T, Sou YS, Mizushima T, Ezaki J, Ueno T et al. Structural basis for sorting mechanism of p62 in selective autophagy. JBiolChem2008; 283: 22847–22857.
70. Ichimura Y, Komatsu M. Selective degradation of p62 by autophagy. Semin Immunopathol 2010; 32: 431–436.
71. Filimonenko M, Isakson P, Finley KD, Anderson M, Jeong H, Melia TJ et al. The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy. Mol Cell 2010; 38: 265–279.
72. Riley BE, Kaiser SE, Shaler TA, Ng AC, Hara T, Hipp MS et al. Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection. JCellBiol2010; 191: 537–552.
73. Fecto F, Yan J, Vemula SP, Liu E, Yang Y, Chen W et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 2011; 68: 1440–1446.
74. Deretic V. A master conductor for aggregate clearance by autophagy. Dev Cell 2010; 18: 694–696.
75. Johnson CW, Melia TJ, Yamamoto A. Modulating macroautophagy: a neuronal perspective. Future Med Chem 2012; 4: 1715–1731.
76. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 2004; 15: 1101–1111.
77. Perry CN, Kyoi S, Hariharan N, Takagi H, Sadoshima J, Gottlieb RA. Novel methods for measuring cardiac autophagy in vivo. Methods Enzymol 2009; 453: 325–342.
78. Liu XD, Ko S, Xu Y, Fattah EA, Xiang Q, Jagannath C et al. Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress. JBiolChem 2012; 287: 19687–19698.
79. Wong ES, Tan JM, Soong WE, Hussein K, Nukina N, Dawson VL et al. Autophagy mediated clearance of aggresomes is not a universal phenom-enon. Hum Mol Genet 2008; 17: 2570–2582.
80. Kirilyuk A, Shimoji M, Catania J, Sahu G, Pattabiraman N, Giordano A et al. An intrinsically disordered region of the acetyltransferase p300 with similarity to prion-like domains plays a role in aggregation. PLoS One 2012; 7: e48243.
81. Johnston JA, Ward CL, Kopito RR. Aggresomes: a cellular response to misfolded proteins. JCellBiol1998; 143: 1883–1898.
82. Yang Q, She H, Gearing M, Colla E, Lee M, Shacka JJ et al. Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science 2009; 323: 124–127.
83. Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero C, Ferrer I, Obeso JA et al. Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol 2010; 67: 1464–1472.
84. Zhang C, Cuervo AM. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 2008; 14: 959–965.
85. Shibata M, Lu T, Furuya T, Degterev A, Mizushima N, Yoshimori T et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. JBiolChem2006; 281: 14474–14485.
86. David DC, Ollikainen N, Trinidad JC, Cary MP, Burlingame AL, Kenyon C. Widespread protein aggregation as an inherent part of aging in C. elegans. PLoS Biology 2010; 8: e1000450.
87. Wang Y, Martinez-Vicente M, Krüger U, Kaushik S, Wong E, Mandelkow EM et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet 2009; 18: 4153–4170.
88. Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H, Fernandez-Carasa I et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci 2013; 16: 394–406.
89. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 2004; 305: 1292–1295.
90. Matsumoto G, Wada K, Okuno M, Kurosawa M, Nukina N. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell 2011; 44: 279–289.
91. Jiang T, Yu JT, Tian Y, Tan L. Epidemiology and etiology of Alzheimer’s disease: from genetic to non-genetic factors. Curr Alzheimer Res 2013; 10: 852–867.
92. De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 2003; 38: 9–12.
93. Kumar P, Ambasta RK, Veereshwarayya V, Rosen KM, Kosik KS, Band H et al. CHIP and HSPs interact with beta-APP in a proteasome-dependent manner and influence Abeta metabolism. Hum Mol Genet 2007; 16: 848–864.
94. Kaneko M, Koike H, Saito R, Kitamura Y, Okuma Y, Nomura Y. Loss of HRD1-mediated protein degradation causes amyloid precursor protein accumulation and amyloid-beta generation. J Neurosci 2010; 30: 3924–3932.
95. Atkin G, Hunt J, Minakawa E, Sharkey L, Tipper N, Tennant W et al. F-box only protein 2 (Fbxo2) regulates amyloid precursor levels and processing. JBiolChem2014; 289: 7038–7048.
96. El Ayadi A, Stieren ES, Barral JM, Boehning D. Ubiquilin-1 regulates amyloid precursor protein maturation and degradation by stimulating K63-linked polyubiquitination of lysine 688. Proc Natl Acad Sci USA 2012; 109: 13416–13421.
97. Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. JBiolChem2008; 283: 29615–29619.
98. Perry G, Friedman R, Shaw G, Chau V. Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc Natl Acad Sci USA 1987; 84: 3033–3036.
99. Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA et al. The autophagy related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. JClinInvest2008; 118: 2190–2199.
100. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006; 441: 880–884.
101. Liang CC, Wang C, Peng X, Gan B, Guan JL. Neural-specific deletionof FIP200 leads to cerebellar degeneration caused by increased neuronal death and axon degeneration. JBiolChem2010; 285: 3499–3509.
102. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A et al. Extensive involvement of autophagy in Alzheimer disease: an immunoe-lectron microscopy study. J Neuropathol Exp Neurol 2005; 64: 113–122.
103. Boland B, Kumar A, Lee S, Platt FM, Wegiel J, Yu WH et al. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J Neurosci 2008; 28: 6926–6937.
104. Nixon RA, Yang DS. Autophagy failure in Alzheimer’s diseasedlocating the primary defect. Neurobiol Dis 2011; 43: 38–45.
105. Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nature Rev Mol Cell Biol 2007; 8: 101–112.
106. Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Sarmiento J, Troncoso J, Jackson GR et al. Identification of oligomers at early stages of tau aggregation in Alzheimer’s disease. FASEB J 2012; 26: 1946–1959.
107. Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci USA 2003; 100: 10032–10037.
108. Canu N, Dus L, Barbato C, Ciotti MT, Brancolini C, Rinaldi AM et al. Tau cleavage and dephosphorylation in cerebellar granule neurons undergoing apoptosis. JNeurosci1998; 18: 7061–7074.
109. Karsten SL, Sang TK, Gehman LT, Chatterjee S, Liu J, Lawless GM et al. A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegenera-tion. Neuron 2006; 51: 549–560.
110. Khlistunova I, Biernat J, Wang Y, Pickhardt M, von Bergen M, Gazova Z et al. Inducible expression of tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs. J Biol Chem 2006; 281: 1205–1214.
111. Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H, Grover A et al. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 2004; 13: 703–714.
112. Scaglione KM, Basrur V, Ashraf NS, Konen JR, Elenitoba-Johnson KS, Todi SV et al. The ubiquitin-conjugating enzyme (E2) Ube2w ubiquiti-nates the N terminus of substrates. J Biol Chem 2013; 288: 18784–18788.
113. Lee MJ, Lee JH, Rubinsztein DC. Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. Prog Neurobiol 2013; 105: 49–59.
114. Hamano T, Gendron TF, Causevic E, Yen SH, Lin WL, Isidoro C et al. Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression. Eur J Neurosci 2008; 27: 1119–1130.
115. Dall'Armi C, Hurtado-Lorenzo A, Tian H, Morel E, Nezu A, Chan RB et al. The phospholipase D1 pathway modulates macroautophagy. Nat Commun 2010; 1: 142.
116. Metcalfe MJ, Huang Q, Figueiredo-Pereira ME. Coordination between proteasome impairment and caspase activation leading to TAU pathology: neuroprotection by cAMP. Cell Death Dis 2012; 3: e326.
117. Rodríguez-Martín T, Cuchillo-Ibáñez I, Noble W, Nyenya F, Anderton BH, Hanger DP. Tau phosphorylation affects its axonal transport and degrada-tion. Neurobiol Aging 2013; 34: 2146–2157.
118. Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA et al. The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 1995; 14: 467–475.
119. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A et al. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 1997; 276: 2045–2047.
120. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S et al. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat Genet 1998; 18: 106–108.
121. Singleton AB, Farrer M, Johnson J, Singleton A, Haque S, Kachergus J et al. α-Synuclein locus triplication causes Parkinson’s disease. Science 2003; 302: 841.
122. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. α-Synuclein in Lewy bodies. Nature 1997; 388: 839–840.
123. Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM et al. Aggregation of α-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 1998; 152: 879–884.
124. Seidel K, Schöls L, Nuber S, Petrasch-Parwez E, Gierga K, Wszolek Z et al. First appraisal of brain pathology owing to A30P mutant alpha-synuclein. Ann Neurol 2010; 67: 684–689.
125. Liu CW, Corboy MJ, DeMartino GN, Thomas PJ. Endoproteolytic activity of the proteasome. Science 2003; 299: 408–411.
126. Luk KC, Kehm V, Carroll J, Zhang B, O'Brien P, Trojanowski JQ et al. Pathological alpha-synuclein transmission initiates Parkinson-like neuro-degeneration in nontransgenic mice. Science 2012; 338: 949–953.
127. Bennett MC, Bishop JF, Leng Y, Chock PB, Chase TN, Mouradian MM. Degradation of alpha-synuclein by proteasome. JBiolChem1999; 274: 33855–33858.
128. Imai Y, Soda M, Takahashi R. Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. JBiol Chem 2000; 275: 35661–35664.
129. McLean PJ, Kawamata H, Hyman BT. Alpha-synucleinenhanced green fluorescent protein fusion proteins form proteasome sensitive inclusions in primary neurons. Neuroscience 2001; 104: 901–912.
130. Tofaris GK, Layfield R, Spillantini MG. Alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the protea-some. FEBS Lett 2001; 509: 22–26.
131. Nakajima T, Takauchi S, Ohara K, Kokai M, Nishii R, Maeda S et al. Alpha-synuclein-positive structures induced in leupeptin-infused rats. Brain Res 2005; 1040: 73–80.
132. Machiya Y, Hara S, Arawaka S, Fukushima S, Sato H, Sakamoto M et al. Phosphorylated alpha-synuclein at Ser-129 is targeted to the proteasome pathway in a ubiquitin independent manner. JBiolChem2010; 285: 40732–40744.
133. Shin Y, Klucken J, Patterson C, Hyman BT, McLean PJ. The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways. JBiolChem2005; 280: 23727–23734.
134. Liani E, Eyal A, Avraham E, Shemer R, Szargel R, Berg D et al. Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease. Proc Natl Acad Sci USA 2004; 101: 5500–5505.
135. Lee JT, Wheeler TC, Li L, Chin LS. Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. Hum Mol Genet 2008; 17: 906–917.
136. Nair VD, McNaught KS, González-Maeso J, Sealfon SC, Olanow CW. p53 mediates nontranscriptional cell death in dopaminergic cells in response to proteasome inhibition. JBiolChem2006; 281: 39550–39560.
137. Mei J, Niu C. Alterations of Hrd1 expression in various encephalic regional neurons in 6-OHDA model of Parkinson's disease. Neurosci Lett 2010; 474: 63–68.
138. Tofaris GK, Kim HT, Hourez R, Jung JW, Kim KP, Goldberg AL. Ubiquitin ligase Nedd4 promotes alpha-synuclein degradation by the endosomal– lysosomal pathway. Proc Natl Acad Sci USA 2011; 108: 17004–17009.
139. Das C, Hoang QQ, Kreinbring CA, Luchansky SJ, Meray RK, Ray SS et al. Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1. Proc Natl Acad Sci USA 2006; 103: 4675–4680.
140. Cartier AE, Ubhi K, Spencer B, Vazquez-Roque RA, Kosberg KA, Four-geaud L et al. Differential effects of UCHL1 modulation on alpha-synuclein in PD-like models of alpha-synucleinopathy. PLoS One 2012; 7: e34713.
141. Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT Jr.. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell 2002; 111: 209–218.
142. Bedford L, Hay D, Devoy A, Paine S, Powe DG, Seth R et al. Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and lewy-like inclusions resembling human pale bodies. JNeurosci2008; 28: 8189–8198.
143. McNaught KS, Jenner P. Proteasomal function is impaired in substantia nigra in Parkinson's disease. Neurosci Lett 2001; 297: 191–194.
144. Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L. Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. JBiolChem2008; 283: 23542–23556.
145. Malkus KA, Ischiropoulos H. Regional deficiencies in chaperone-mediated autophagy underlie alpha-synuclein aggregation and neurodegeneration. Neurobiol Dis 2012; 46: 732–744.
146. Shen YF, Tang Y, Zhang XJ, Huang KX, Le WD. Adaptive changes in autophagy after UPS impairment in Parkinson’s disease.Acta Pharmacol Sin 2013; 34: 667–673.
147. Sevlever D, Jiang P, Yen SH. Cathepsin D is the main lysosomal enzyme involved in the degradation of alpha-synuclein and generation of its carboxy-terminally truncated species. Biochemistry 2008; 47: 9678–9687.
148. Cullen V, Lindfors M, Ng J, Paetau A, Swinton E, Kolodziej P et al. Cathepsin D expression level affects alpha-synuclein processing, aggrega-tion, and toxicity in vivo. Mol Brain 2009; 2: 5.
149. Paxinou E, Chen Q, Weisse M, Giasson BI, Norris EH, Rueter SM et al. Induction of alpha-synuclein aggregation by intracellular nitrative insult. J Neurosci 2001; 21: 8053–8061.
150. Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurode-generative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. J Neurosci 2009; 29: 13578–13588.
151. Munoz-Sanjuan I, Bates GP. The importance of integrating basic and clinical research toward the development of new therapies for Huntington disease. JClinInvest2011; 121: 476–483.
152. Walker FO. Huntington's disease. Lancet 2007; 369: 218–228.
153. Arrasate M, Finkbeiner S. Protein aggregates in Huntington’s disease.Exp Neurol 2012; 238: 1–11.
154. Warby SC, Visscher H, Collins JA, Doty CN, Carter C, Butland SL et al. HTT haplotypes contribute to differences in Huntington disease preva-lence between Europe and East Asia. Eur J Hum Genet 2011; 19: 561–566.
155. Williams AJ, Paulson HL. Polyglutamine neurodegeneration: protein misfolding revisited. Trends Neurosci 2008; 31: 521–528.
156. Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nature Rev Neurosci 2003; 4: 49–60.
157. Miller J, Arrasate M, Brooks E, Libeu CP, Legleiter J, Hatters D et al. Identifying polyglutamine protein species in situ that best predict neurodegeneration. Nat Chem Biol 2011; 7: 925–934.
158. Kar K, Jayaraman M, Sahoo B, Kodali R, Wetzel R. Critical nucleus size for disease-related polyglutamine aggregation is repeat-length dependent. Nat Struct Mol Biol 2011; 18: 328–336.
159. Qi L, Zhang XD, Wu JC, Lin F, Wang J, DiFiglia M et al. The role of chaperone–mediated autophagy in huntingtin degradation. PLoS ONE 2012; 7: e46834.
160. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dys-trophic neurites in brain. Science 1997; 277: 1990–1993.
161. Hipp MS, Patel CN, Bersuker K, Riley BE, Kaiser SE, Shaler TA et al. Indirect inhibition of 26S proteasome activity in a cellular model of Huntington’s disease. JCellBiol2012; 196: 573–587.
162. Jeong H, Then F, Melia TJ Jr., Mazzulli JR, Cui L, Savas JN et al. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 2009; 137: 60–72.
163. Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci 2010; 13: 567–576.
164. Wong E, Cuervo AM. Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 2010; 13: 805–811.
165. Lee H, Noh JY, Oh Y, Kim Y, Chang JW, Chung CW et al. IRE1 plays an essential role in ER stress-mediated aggregation of mutant huntingtin via the inhibition of autophagy flux. Hum Mol Genet 2012; 21: 101–114.
166. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG et al. Inhibition of mTOR induces autophagy and reduces toxicity of polygluta-mine expansions in fly and mouse models of Huntington disease. Nat Genet 2004; 36: 585–595.
167. Kovacs GG, Budka H. Prion diseases: from protein to cell pathology. Am J Pathol 2008; 172: 555–565.
168. Ma J, Wang F. Prion disease and the ‘protein-only hypothesis’. Essays Biochem 2014; 56: 181–191.
169. Wells GA, Scott AC, Johnson CT, Gunning RF, Hancock RD, Jeffrey M et al. A novel progressive spongiform encephalopathy in cattle. Vet Rec 1987; 121: 419–420.
170. Williams ES, Young S. Spongiform encephalopathy of Rocky Mountain elk. JWildlDis1982; 18: 465–471.
171. Wyatt JM, Pearson GR, Smerdon TN, Gruffydd-Jones TJ, Wells GA, Wilesmith JW. Naturally occurring scrapie-like spongiform encephalopa-thy in five domestic cats. Vet Rec 1991; 129: 233–236.
172. Gajdusek DC, Gibbs CJ, Alpers M. Experimental transmission of a Kuru-like syndrome to chimpanzees. Nature 1966; 209: 794–796.
173. Gibbs CJ Jr., Gajdusek DC, Asher DM, Alpers MP, Beck E, Daniel PM et al. Creutzfeldt–Jakob disease (spongiform encephalopathy): transmission to the chimpanzee. Science 1968; 161: 388–389.
174. Masters CL, Gajdusek DC, Gibbs CJ Jr.. Creutzfeldt–Jakob disease virus isolations from the Gerstmann–Straussler syndrome with an analysis of the various forms of amyloid plaque deposition in the virus-induced spongi-form encephalopathies. Brain 1981; 104: 559–588.
175. Lugaresi E, Medori R, Montagna P, Baruzzi A, Cortelli P, Lugaresi A et al. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. NEnglJMed1986; 315: 997–1003.
176. Legname G, Baskakov IV, Nguyen HO, Riesner D, Cohen FE, DeArmond SJ et al. Synthetic mammalian prions. Science 2004; 305: 673–676.
177. Castilla J, Saá P, Hetz C, Soto C. In vitro generation of infectious scrapie prions. Cell 2005; 121: 195–206.
178. Wang F, Wang X, Yuan CG, Ma J. Generating a prion with bacterially expressed recombinant prion protein. Science 2010; 327: 1132–1135.
179. Saborio GP, Permanne B, Soto C. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 2001; 411: 810–813.
180. Soto C. Transmissible proteins: expanding the prion heresy. Cell 2012; 149: 968–977.
181. Shorter J, Lindquist S. Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformers. Science 2004; 304: 1793–1797.
182. DebBurman SK, Raymond GJ, Caughey B, Lindquist S. Chaperone-supervised conversion of prion protein to its protease-resistant form. Proc Natl Acad Sci USA 1997; 94: 13938–13943.
183. Wilkins S, Choglay AA, Chapple JP, van der Spuy J, Rhie A, Birkett CR et al. The binding of the molecular chaperone Hsc70 to the prion protein PrP is modulated by pH and copper. Int J Biochem Cell Biol 2010; 42: 1226–1232.
184. Förster A, Masters EI, Whitby FG, Robinson H, Hill CP. The 1.9 Å structure of a proteasome-11S activator complex and implications for proteasome-PAN/PA700 interactions. Mol Cell 2005; 18: 589–599.
185. Deriziotis P, André R, Smith DM, Goold R, Kinghorn KJ, Kristiansen M et al. Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry. EMBO J 2011; 30: 3065–3077.
186. Boellaard JW, Kao M, Schlote W, Diringer H. Neuronal autophagy in experimental scrapie. Acta Neuropathol 1991; 82: 225–228.
187. Sikorska B, Liberski PP, Brown P. Neuronal autophagy and aggresomes constitute a consistent part of neurodegeneration in experimental scrapie. Folia Neuropathol 2007; 45: 170–178.
188. Mishra RS, Bose S, Gu Y, Li R, Singh N. Aggresome formation by mutant prion proteins: the unfolding role of proteasomes in familial prion disorders. JAlzheimersDis2003; 5: 15–23.
189. Heitz S, Grant NJ, Bailly Y. Doppel induces autophagic stress in prion protein-deficient Purkinje cells. Autophagy 2009; 5: 422–424.
190. Heiseke A, Aguib Y, Schatzl HM. Autophagy, prion infection and their mutual interactions. Curr Issues Mol Biol 2010; 12: 87–97.
191. Aguib Y, Heiseke A, Gilch S, Riemer C, Baier M, Schatzl HM et al. Autophagy induction by trehalose counteracts cellular prion infection. Autophagy 2009; 5: 361–369.
192. Moughamian AJ, Holzbaur EL. Dynactin is required for transport initiation from the distal axon. Neuron 2012; 74: 331–343.
193. Ikenaka K, Kawai K, Katsuno M, Huang Z, Jiang YM, Iguchi Y et al. dnc-1/ dynactin 1 knockdown disrupts transport of autophagosomes and induces motor neuron degeneration. PLoS One 2013; 8: e54511.
194. Fecto F, Siddique T. UBQLN2/P62 cellular recycling pathways in amyotrophic lateral sclerosis and frontotemporal dementia. Muscle Nerve 2012; 45: 157–162.
195. Guo Y, Li C, Wu D, Wu S, Yang C, Liu Y et al. Ultrastructural diversity of inclusions and aggregations in the lumbar spinal cord of SOD1-G93A transgenic mice. Brain Res 2010; 1353: 234–244.
196. Beleza-Meireles A, Al-Chalabi A. Genetic studies of amyotrophic lateral sclerosis: controversies and perspectives. Amyotroph Lateral Scler 2009; 10: 1–14.
197. Buratti E, Baralle FE. Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci 2008; 13: 867–878.
198. Johnson BS, Snead D, Lee JJ, McCaffery JM, Shorter J, Gitler AD. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem 2009; 284: 20329–20339.
199. Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 1997; 18: 327–338.
200. Bendotti C, Atzori C, Piva R, Tortarolo M, Strong MJ, Debiasi S et al. Activated p38MAPK is a novel component of the intracellular inclusions found in human amyotrophic lateral sclerosis and mutant SOD1 transgenic mice. J Neuropathol Exp Neurol 2004; 63: 113–119.
201. Leigh PN, Whitwell H, Garofalo O, Buller J, Swash M, Martin JE et al. Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity. Brain 1991; 114: 775–788.
202. Mendonca DM, Chimelli L, Martinez AM. Expression of ubiquitin and proteasome in motorneurons and astrocytes of spinal cords from patients with amyotrophic lateral sclerosis. Neurosci Lett 2006; 404: 315–319.
203. Sasaki S. Endoplasmic reticulum stress in motor neurons of the spinal cord in sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 2010; 69: 346–355.
204. Watanabe M, Dykes-Hoberg M, Culotta VC, Price DL, Wong PC, Rothstein JD. Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol Dis 2001; 8: 933–941.
205. Morimoto N, Nagai M, Ohta Y, Miyazaki K, Kurata T, Morimoto M et al. Increased autophagy in transgenic mice with a G93A mutant SOD1 gene. Brain Res 2007; 1167: 112–117.
206. Di Noto L, Whitson LJ, Cao X, Hart PJ, Levine RL. Proteasomal degradation of mutant superoxide dismutases linked to amyotrophic lateral sclerosis. JBiolChem2005; 280: 39907–39913.
207. Hoffman EK, Wilcox HM, Scott RW, Siman R. Proteasome inhibition enhances the stability of mouse Cu/Zn superoxide dismutase with mutations linked to familial amyotrophic lateral sclerosis. JNeurolSci 1996; 139: 15–20.
208. Hyun DH, Lee M, Halliwell B, Jenner P. Proteasomal inhibition causes the formation of protein aggregates containing a wide range of proteins, including nitrated proteins. JNeurochem2003; 86: 363–373.
209. Puttaparthi K, Wojcik C, Rajendran B, DeMartino GN, Elliott JL. Aggregate formation in the spinal cord of mutant SOD1 transgenic mice is reversible and mediated by proteasomes 1. J Neurochem 2003; 87: 851–860.
210. Carra S, Crippa V, Rusmini P, Boncoraglio A, Minoia M, Giorgetti E et al. Alteration of protein folding and degradation in motor neuron diseases: implications and protective functions of small heat shock proteins. Prog Neurobiol 2012; 97: 83–100.
211. Carra S, Rusmini P, Crippa V, Giorgetti E, Boncoraglio A, Naujock N et al. Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders. Philos Trans R Soc Lond B Biol Sci 2013; 368: 20110409.
212. Zhang X, Li L, Chen S, Yang D, Wang Y, Zhang X et al. Rapamycin treatment augments motor neuron degeneration in SOD1G93A mouse model of amyotrophic lateral sclerosis. Autophagy 2011; 7: 412–425.
213. Crippa V, Sau D, Rusmini P, Boncoraglio A, Onesto E, Bolzoni E et al. The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS). Hum Mol Genet 2010; 19: 3440–3456.
214. Sarkar S, Rubinsztein DC. Huntington's disease: degradation of mutant huntingtin by autophagy. FEBS J 2008; 275: 4263–4270.
215. Ravikumar B, Duden R, Rubinsztein DC. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 2002; 11: 1107–1117.
216. Domanskyi A, Geissler C, Vinnikov IA, Alter H, Schober A, Vogt MA et al. Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson’s disease models. FASEB J 2011; 25: 2898–2910.
217. Rose C, Menzies FM, Renna M, Acevedo-Arozena A, Corrochano S, Sadig O et al. Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington’s disease. Hum Mol Genet 2010; 19: 2144–2153.
218. Sarkar S, Floto RA, Berger Z, Imarisio S, Cordenier A, Pasco M et al. Lithium induces autophagy by inhibiting inositol monophosphatase. JCell Biol 2005; 170: 1101–1111.
219. Feng HL, Leng Y, Ma CH, Zhang J, Ren M, Chuang DM. Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 2008; 155: 567–572.
220. Pizzasegola C, Caron I, Daleno C, Ronchi A, Minoia C, Carrì MT et al. Treatment with lithium carbonate does not improve disease progression in two different strains of SOD1 mutant mice. Amyotroph Lateral Scler 2009; 10: 221–228.
221. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant Huntingtin and alpha-synuclein. J Biol Chem 2007; 282: 5641–5652.
222. Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 2004; 10: 148–154.
223. Maher P, Dargusch R, Ehren JL, Okada S, Sharma K, Schubert D et al. Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes. PLoS One 2011; 6: e21226.
224. Magnaudeix A, Wilson CM, Page G, Bauvy C, Codogno P, Lévêque P et al. PP2A blockade inhibits autophagy and causes intraneuronal accumulation of ubiquitinated proteins. Neurobiol Aging 2013; 34: 770–790.
225. Jia H, Kast RJ, Steffan JS, Thomas EA. Selective histone deacetylase (HDAC) inhibition imparts beneficial effects in Huntington’s disease mice: implications for the ubiquitin-proteasomal and autophagy systems. Hum Mol Genet 2012; 21: 5280–5293.
226. Wang X, Robbins J. Proteasomal and lysosomal protein degradation and heart disease. J Mol Cell Cardiol 2014; 71: 16–24.
227. Chesser AS, Pritchard SM, Johnson GW. Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease. Front Neurol 2013; 4: 1–12.
228. Xilouri M, Brekk OR, Stefanis L. Alpha-synuclein and protein degradation systems: a reciprocal relationship. Mol Neurobiol 2013; 47: 537–551.