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Protein degradation pathways in Parkinson’s disease: curse or blessing

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Abstract

Protein misfolding, aggregation and deposition are common disease mechanisms in many neurodegenerative diseases including Parkinson’s disease (PD). Accumulation of damaged or abnormally modified proteins may lead to perturbed cellular function and eventually to cell death. Thus, neurons rely on elaborated pathways of protein quality control and removal to maintain intracellular protein homeostasis. Molecular chaperones, the ubiquitin–proteasome system (UPS) and the autophagy–lysosomal pathway (ALP) are critical pathways that mediate the refolding or removal of abnormal proteins. The successive failure of these protein degradation pathways, as a cause or consequence of early pathological alterations in vulnerable neurons at risk, may present a key step in the pathological cascade that leads to spreading neurodegeneration. A growing number of studies in disease models and patients have implicated dysfunction of the UPS and ALP in the pathogenesis of Parkinson’s disease and related disorders. Deciphering the exact mechanism by which the different proteolytic systems contribute to the elimination of pathogenic proteins, like α-synuclein, is therefore of paramount importance. We herein review the role of protein degradation pathways in Parkinson’s disease and elaborate on the different contributions of the UPS and the ALP to the clearance of altered proteins. We examine the interplay between different degradation pathways and provide a model for the role of the UPS and ALP in the evolution and progression of α-synuclein pathology. With regards to exciting recent studies we also discuss the putative potential of using protein degradation pathways as novel therapeutic targets in Parkinson’s disease.

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References

  1. Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero C, Ferrer I, Obeso JA, Schapira AH (2010) Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol 67(12):1464–1472. doi:10.1001/archneurol.2010.198

    Article  PubMed  Google Scholar 

  2. Alvarez-Erviti L, Seow Y, Schapira AH, Gardiner C, Sargent IL, Wood MJ, Cooper JM (2011) Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis 42:360–367. doi:10.1016/j.nbd.2011.01.029

    Article  PubMed  CAS  Google Scholar 

  3. Ancolio K, Alves da Costa C, Ueda K, Checler F (2000) Alpha-synuclein and the Parkinson’s disease-related mutant Ala53Thr-alpha-synuclein do not undergo proteasomal degradation in HEK293 and neuronal cells. Neurosci Lett 285(2):79–82. pii:S0304-3940(00)01049-1

    Google Scholar 

  4. Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, Mouatt-Prigent A, Ruberg M, Hirsch EC, Agid Y (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12(1):25–31

    PubMed  CAS  Google Scholar 

  5. Arias E, Cuervo AM (2011) Chaperone-mediated autophagy in protein quality control. Curr Opin Cell Biol 23(2):184–189

    Google Scholar 

  6. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431(7010):805–810. doi:10.1038/nature02998

    Article  PubMed  CAS  Google Scholar 

  7. Barrachina M, Castano E, Dalfo E, Maes T, Buesa C, Ferrer I (2006) Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies. Neurobiol Dis 22(2):265–273. doi:10.1016/j.nbd.2005.11.005

    Article  PubMed  CAS  Google Scholar 

  8. Batelli S, Peverelli E, Rodilossi S, Forloni G, Albani D (2011) Macroautophagy and the proteasome are differently involved in the degradation of alpha-synuclein wild type and mutated A30P in an in vitro inducible model (PC12/TetOn). Neuroscience 195:128–137

  9. Bedford L, Hay D, Devoy A, Paine S, Powe DG, Seth R, Gray T, Topham I, Fone K, Rezvani N, Mee M, Soane T, Layfield R, Sheppard PW, Ebendal T, Usoskin D, Lowe J, Mayer RJ (2008) Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J Neurosci 28(33):8189–8198. doi:10.1523/JNEUROSCI.2218-08.2008

    Article  PubMed  CAS  Google Scholar 

  10. Bennett MC, Bishop JF, Leng Y, Chock PB, Chase TN, Mouradian MM (1999) Degradation of alpha-synuclein by proteasome. J Biol Chem 274(48):33855–33858

    Article  PubMed  CAS  Google Scholar 

  11. Berthet A, Bezard E, Porras G, Fasano S, Barroso-Chinea P, Dehay B et al (2012) L-DOPA impairs proteasome activity in Parkinsonism through D1 dopamine receptor. J Neurosci 32(2):681–691

    Google Scholar 

  12. Betarbet R, Canet-Aviles RM, Sherer TB, Mastroberardino PG, McLendon C, Kim JH, Lund S, Na HM, Taylor G, Bence NF, Kopito R, Seo BB, Yagi T, Yagi A, Klinefelter G, Cookson MR, Greenamyre JT (2006) Intersecting pathways to neurodegeneration in Parkinson’s disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin–proteasome system. Neurobiol Dis 22(2):404–420. doi:10.1016/j.nbd.2005.12.003

    Article  PubMed  CAS  Google Scholar 

  13. Biasini E, Fioriti L, Ceglia I, Invernizzi R, Bertoli A, Chiesa R, Forloni G (2004) Proteasome inhibition and aggregation in Parkinson’s disease: a comparative study in untransfected and transfected cells. J Neurochem 88(3):545–553

    Article  PubMed  CAS  Google Scholar 

  14. Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, Johansen T (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171(4):603–614. doi:10.1083/jcb.200507002

    Article  PubMed  CAS  Google Scholar 

  15. Blandini F, Sinforiani E, Pacchetti C, Samuele A, Bazzini E, Zangaglia R, Nappi G, Martignoni E (2006) Peripheral proteasome and caspase activity in Parkinson disease and Alzheimer disease. Neurology 66(4):529–534. doi:10.1212/01.wnl.0000198511.09968.b3

    Article  PubMed  CAS  Google Scholar 

  16. Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT, McLean PJ, Young AB, Housman DE, Kazantsev AG (2006) Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington’s and Parkinson’s diseases. Proc Natl Acad Sci USA 103(11):4246–4251. doi:10.1073/pnas.0511256103

    Article  PubMed  CAS  Google Scholar 

  17. Bove J, Martinez-Vicente M, Vila M (2011) Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci 12(8):437–452. doi:10.1038/nrn3068

    Article  PubMed  CAS  Google Scholar 

  18. Bove J, Zhou C, Jackson-Lewis V, Taylor J, Chu Y, Rideout HJ, Wu DC, Kordower JH, Petrucelli L, Przedborski S (2006) Proteasome inhibition and Parkinson’s disease modeling. Ann Neurol 60(2):260–264. doi:10.1002/ana.20937

    Article  PubMed  CAS  Google Scholar 

  19. Brighina L, Prigione A, Begni B, Galbussera A, Andreoni S, Piolti R, Ferrarese C (2010) Lymphomonocyte alpha-synuclein levels in aging and in Parkinson disease. Neurobiol Aging 31(5):884–885. doi:10.1016/j.neurobiolaging.2008.06.010

    Article  PubMed  CAS  Google Scholar 

  20. Bukhatwa S, Zeng BY, Rose S, Jenner P (2010) A comparison of changes in proteasomal subunit expression in the substantia nigra in Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy. Brain Res 1326:174–183. doi:10.1016/j.brainres.2010.02.045

    Article  PubMed  CAS  Google Scholar 

  21. Caneda-Ferron B, De Girolamo LA, Costa T, Beck KE, Layfield R, Billett EE (2008) Assessment of the direct and indirect effects of MPP+ and dopamine on the human proteasome: implications for Parkinson’s disease aetiology. J Neurochem 105(1):225–238. doi:10.1111/j.1471-4159.2007.05130.x

    Article  PubMed  CAS  Google Scholar 

  22. Casarejos MJ, Solano RM, Gomez A, Perucho J, de Yebenes JG, Mena MA (2011) The accumulation of neurotoxic proteins, induced by proteasome inhibition, is reverted by trehalose, an enhancer of autophagy, in human neuroblastoma cells. Neurochem Int 58(4):512–520. doi:10.1016/j.neuint.2011.01.008

    Article  PubMed  CAS  Google Scholar 

  23. Chen L, Feany MB (2005) Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 8(5):657–663. doi:10.1038/nn1443

    Article  PubMed  CAS  Google Scholar 

  24. Chen L, Thiruchelvam MJ, Madura K, Richfield EK (2006) Proteasome dysfunction in aged human alpha-synuclein transgenic mice. Neurobiol Dis 23(1):120–126. doi:10.1016/j.nbd.2006.02.004

    Article  PubMed  CAS  Google Scholar 

  25. Chen Q, Thorpe J, Keller JN (2005) Alpha-synuclein alters proteasome function, protein synthesis, and stationary phase viability. J Biol Chem 280(34):30009–30017. doi:10.1074/jbc.M501308200

    Article  PubMed  CAS  Google Scholar 

  26. Chew KC, Ang ET, Tai YK, Tsang F, Lo SQ, Ong E, Ong WY, Shen HM, Lim KL, Dawson VL, Dawson TM, Soong TW (2011) Enhanced autophagy from chronic toxicity of iron and mutant A53T alpha-synuclein: implications for neuronal cell death in Parkinson disease. J Biol Chem 286(38):33380–33389. doi:10.1074/jbc.M111.268409

    Article  PubMed  CAS  Google Scholar 

  27. Chou AP, Li S, Fitzmaurice AG, Bronstein JM (2010) Mechanisms of rotenone-induced proteasome inhibition. Neurotoxicology 31(4):367–372

    Google Scholar 

  28. Choubey V, Safiulina D, Vaarmann A, Cagalinec M, Wareski P, Kuum M, Zharkovsky A, Kaasik A (2011) Mutant A53T alpha-synuclein induces neuronal death by increasing mitochondrial autophagy. J Biol Chem 286(12):10814–10824. doi:10.1074/jbc.M110.132514

    Article  PubMed  CAS  Google Scholar 

  29. Chu Y, Dodiya H, Aebischer P, Olanow CW, Kordower JH (2009) Alterations in lysosomal and proteasomal markers in Parkinson’s disease: relationship to alpha-synuclein inclusions. Neurobiol Dis 35(3):385–398. doi:10.1016/j.nbd.2009.05.023

    Article  PubMed  CAS  Google Scholar 

  30. Claessen JH, Kundrat L, Ploegh HL (2012) Protein quality control in the ER: balancing the ubiquitin checkbook. Trends Cell Biol 22(1):22–32. doi:10.1016/j.tcb.2011.09.010

    Article  PubMed  CAS  Google Scholar 

  31. Corrochano S, Renna M, Carter S, Chrobot N, Kent R, Stewart M, Cooper J, Brown SD, Rubinsztein DC, Acevedo-Arozena A (2012) Alpha-synuclein levels modulate Huntington’s disease in mice. Hum Mol Genet 21:485–494. doi:10.1093/hmg/ddr477

    Google Scholar 

  32. Crews L, Spencer B, Desplats P, Patrick C, Paulino A, Rockenstein E, Hansen L, Adame A, Galasko D, Masliah E (2010) Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS One 5(2):e9313. doi:10.1371/journal.pone.0009313

    Article  PubMed  CAS  Google Scholar 

  33. 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. doi:10.1126/science.1101738.305/5688/1292

    Article  PubMed  CAS  Google Scholar 

  34. Cullen V, Sardi SP, Ng J, Xu YH, Sun Y, Tomlinson JJ, Kolodziej P, Kahn I, Saftig P, Woulfe J, Rochet JC, Glicksman MA, Cheng SH, Grabowski GA, Shihabuddin LS, Schlossmacher MG (2011) Acid beta-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter alpha-synuclein processing. Ann Neurol 69(6):940–953. doi:10.1002/ana.22400

    Article  PubMed  CAS  Google Scholar 

  35. Dehay B, Bove J, Rodriguez-Muela N, Perier C, Recasens A, Boya P, Vila M (2010) Pathogenic lysosomal depletion in Parkinson’s disease. J Neurosci 30(37):12535–12544. doi:10.1523/JNEUROSCI.1920-10.2010

    Article  PubMed  CAS  Google Scholar 

  36. Dimant H, Ebrahimi-Fakhari D, McLean PJ (2012) Molecular chaperones and co-chaperones in Parkinson’s disease. Neuroscientist (in press)

  37. Ding Q, Dimayuga E, Martin S, Bruce-Keller AJ, Nukala V, Cuervo AM, Keller JN (2003) Characterization of chronic low-level proteasome inhibition on neural homeostasis. J Neurochem 86(2):489–497

    Article  PubMed  CAS  Google Scholar 

  38. Ding WX, Ni HM, Gao W, Yoshimori T, Stolz DB, Ron D, Yin XM (2007) Linking of autophagy to ubiquitin–proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 171(2):513–524. doi:10.2353/ajpath.2007.070188

    Article  PubMed  CAS  Google Scholar 

  39. Ebrahimi-Fakhari D, Cantuti-Castelvetri I, Fan Z, Rockenstein E, Masliah E, Hyman BT, McLean PJ, Unni VK (2011) Distinct roles in vivo for the ubiquitin–proteasome system and the autophagy–lysosomal pathway in the degradation of {alpha}-synuclein. J Neurosci 31(41):14508–14520. doi:10.1523/JNEUROSCI.1560-11.2011

    Article  PubMed  CAS  Google Scholar 

  40. Ebrahimi-Fakhari D, McLean PJ, Unni VK (2012) Alpha-synuclein’s degradation in vivo: opening a new (cranial) window on the roles of degradation pathways in Parkinson disease. Autophagy 8(2):281–283. doi:10.4161/auto.8.2.18938

    Article  PubMed  CAS  Google Scholar 

  41. Ebrahimi-Fakhari D, Wahlster L, McLean PJ (2011) Molecular chaperones in Parkinson’s disease—present and future. J Parkinsons Dis 1(4):299–320

    PubMed  Google Scholar 

  42. Edelmann MJ, Nicholson B, Kessler BM (2011) Pharmacological targets in the ubiquitin system offer new ways of treating cancer, neurodegenerative disorders and infectious diseases. Expert Rev Mol Med 13:e35. doi:10.1017/S1462399411002031

    Article  PubMed  Google Scholar 

  43. Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH, Stefanis L, Vekrellis K (2010) Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 30(20):6838–6851. doi:10.1523/JNEUROSCI.5699-09.2010

    Article  PubMed  CAS  Google Scholar 

  44. Emmanouilidou E, Stefanis L, Vekrellis K (2010) Cell-produced alpha-synuclein oligomers are targeted to, and impair, the 26S proteasome. Neurobiol Aging 31(6):953–968. doi:10.1016/j.neurobiolaging.2008.07.008

    Article  PubMed  CAS  Google Scholar 

  45. Fornai F, Lenzi P, Gesi M, Ferrucci M, Lazzeri G, Busceti CL, Ruffoli R, Soldani P, Ruggieri S, Alessandri MG, Paparelli A (2003) Fine structure and biochemical mechanisms underlying nigrostriatal inclusions and cell death after proteasome inhibition. J Neurosci 23(26):8955–8966

    PubMed  CAS  Google Scholar 

  46. Fornai F, Schluter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, Lazzeri G, Busceti CL, Pontarelli F, Battaglia G, Pellegrini A, Nicoletti F, Ruggieri S, Paparelli A, Sudhof TC (2005) Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin–proteasome system and alpha-synuclein. Proc Natl Acad Sci USA 102(9):3413–3418. doi:10.1073/pnas.0409713102

    Article  PubMed  CAS  Google Scholar 

  47. Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, Holstein GR, Yue Z (2012) Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK2 in the brain. J Neurosci 32(22):7585–7593. doi:10.1523/JNEUROSCI.5809-11.2012

    Article  PubMed  CAS  Google Scholar 

  48. Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T (2008) The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 19(5):2092–2100. doi:10.1091/mbc.E07-12-1257

    Article  PubMed  CAS  Google Scholar 

  49. Furukawa Y, Vigouroux S, Wong H, Guttman M, Rajput AH, Ang L, Briand M, Kish SJ, Briand Y (2002) Brain proteasomal function in sporadic Parkinson’s disease and related disorders. Ann Neurol 51(6):779–782. doi:10.1002/ana.10207

    Article  PubMed  Google Scholar 

  50. Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426(6968):895–899. doi:10.1038/nature02263

    Article  PubMed  CAS  Google Scholar 

  51. Gomez-Suaga P, Luzon-Toro B, Churamani D, Zhang L, Bloor-Young D, Patel S, Woodman PG, Churchill GC, Hilfiker S (2011) Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum Mol Genet 21(3):511–525. doi:10.1093/hmg/ddr481

    Article  PubMed  CAS  Google Scholar 

  52. Gosavi N, Lee HJ, Lee JS, Patel S, Lee SJ (2002) Golgi fragmentation occurs in the cells with prefibrillar alpha-synuclein aggregates and precedes the formation of fibrillar inclusion. J Biol Chem 277(50):48984–48992. doi:10.1074/jbc.M208194200

    Article  PubMed  CAS  Google Scholar 

  53. Grunblatt E, Mandel S, Jacob-Hirsch J, Zeligson S, Amariglo N, Rechavi G, Li J, Ravid R, Roggendorf W, Riederer P, Youdim MB (2004) Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin–proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes. J Neural Transm 111(12):1543–1573. doi:10.1007/s00702-004-0212-1

    Article  PubMed  CAS  Google Scholar 

  54. Hansen C, Angot E, Bergstrom AL, Steiner JA, Pieri L, Paul G, Outeiro TF, Melki R, Kallunki P, Fog K, Li JY, Brundin P (2011) Alpha-synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 121(2):715–725. doi:10.1172/JCI43366

    Article  PubMed  CAS  Google Scholar 

  55. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441(7095):885–889. doi:10.1038/nature04724

    Article  PubMed  CAS  Google Scholar 

  56. Harris H, Rubinsztein DC (2011) Control of autophagy as a therapy for neurodegenerative disease. Nat Rev Neurol 8(2):108–117. doi:10.1038/nrneurol.2011.200

    Article  PubMed  CAS  Google Scholar 

  57. Higashi S, Moore DJ, Minegishi M, Kasanuki K, Fujishiro H, Kabuta T, Togo T, Katsuse O, Uchikado H, Furukawa Y, Hino H, Kosaka K, Sato K, Arai H, Wada K, Iseki E (2011) Localization of MAP1-LC3 in vulnerable neurons and Lewy bodies in brains of patients with dementia with Lewy bodies. J Neuropathol Exp Neurol 70(4):264–280. doi:10.1097/NEN.0b013e318211c86a

    Article  PubMed  CAS  Google Scholar 

  58. Higashi S, Moore DJ, Yamamoto R, Minegishi M, Sato K, Togo T, Katsuse O, Uchikado H, Furukawa Y, Hino H, Kosaka K, Emson PC, Wada K, Dawson VL, Dawson TM, Arai H, Iseki E (2009) Abnormal localization of leucine-rich repeat kinase 2 to the endosomal–lysosomal compartment in lewy body disease. J Neuropathol Exp Neurol 68(9):994–1005. doi:10.1097/NEN.0b013e3181b44ed8

    Article  PubMed  Google Scholar 

  59. Ii K, Ito H, Tanaka K, Hirano A (1997) Immunocytochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly. J Neuropathol Exp Neurol 56(2):125–131

    Article  PubMed  CAS  Google Scholar 

  60. Iwata A, Riley BE, Johnston JA, Kopito RR (2005) HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J Biol Chem 280(48):40282–40292. doi:10.1074/jbc.M508786200

    Article  PubMed  CAS  Google Scholar 

  61. Jahreiss L, Menzies FM, Rubinsztein DC (2008) The itinerary of autophagosomes: from peripheral formation to kiss-and-run fusion with lysosomes. Traffic 9(4):574–587. doi:10.1111/j.1600-0854.2008.00701.x

    Article  PubMed  CAS  Google Scholar 

  62. Johansen T, Lamark T (2011) Selective autophagy mediated by autophagic adapter proteins. Autophagy 7(3):279–296

    Article  PubMed  CAS  Google Scholar 

  63. Kalia SK, Kalia LV, McLean PJ (2010) Molecular chaperones as rational drug targets for Parkinson’s disease therapeutics. CNS Neurol Disord Drug Targets 9(6):741–753

    PubMed  CAS  Google Scholar 

  64. Karpinar DP, Balija MB, Kugler S, Opazo F, Rezaei-Ghaleh N, Wender N, Kim HY, Taschenberger G, Falkenburger BH, Heise H, Kumar A, Riedel D, Fichtner L, Voigt A, Braus GH, Giller K, Becker S, Herzig A, Baldus M, Jackle H, Eimer S, Schulz JB, Griesinger C, Zweckstetter M (2009) Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson’s disease models. EMBO J 28(20):3256–3268. doi:10.1038/emboj.2009.257

    Article  PubMed  CAS  Google Scholar 

  65. Kaushik S, Massey AC, Mizushima N, Cuervo AM (2008) Constitutive activation of chaperone-mediated autophagy in cells with impaired macroautophagy. Mol Biol Cell 19(5):2179–2192. doi:10.1091/mbc.E07-11-1155

    Article  PubMed  CAS  Google Scholar 

  66. Keller JN, Huang FF, Dimayuga ER, Maragos WF (2000) Dopamine induces proteasome inhibition in neural PC12 cell line. Free Radic Biol Med 29(10):1037–1042

    Article  PubMed  CAS  Google Scholar 

  67. Kim YH, Rane A, Lussier S, Andersen JK (2011) Lithium protects against oxidative stress-mediated cell death in alpha-synuclein-overexpressing in vitro and in vivo models of Parkinson’s disease. J Neurosci Res 89(10):1666–1675. doi:10.1002/jnr.22700

    Article  PubMed  CAS  Google Scholar 

  68. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile Parkinsonism. Nature 392(6676):605–608. doi:10.1038/33416

    Article  PubMed  CAS  Google Scholar 

  69. Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8(11):931–937. doi:10.1038/nrm2245

    Article  PubMed  CAS  Google Scholar 

  70. Klionsky DJ, Cuervo AM, Dunn WA Jr, Levine B, van der Klei I, Seglen PO (2007) How shall I eat thee? Autophagy 3(5):413–416

    PubMed  Google Scholar 

  71. Klucken J, Poehler AM, Ebrahimi-Fakhari D, Schneider J, Nuber S, Rockenstein E, Schlotzer-Schrehardt U, Hyman BT, McLean PJ, Masliah E, Winkler J (2012) Alpha-synuclein aggregation involves a bafilomycin A 1-sensitive autophagy pathway. Autophagy 8(5)

  72. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441(7095):880–884. doi:10.1038/nature04723

    Article  PubMed  CAS  Google Scholar 

  73. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Kominami E, Tanaka K (2007) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131(6):1149–1163. doi:10.1016/j.cell.2007.10.035

    Article  PubMed  CAS  Google Scholar 

  74. Komatsu M, Wang QJ, Holstein GR, Friedrich VL Jr, Iwata J, Kominami E, Chait BT, Tanaka K, Yue Z (2007) Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc Natl Acad Sci USA 104(36):14489–14494. doi:10.1073/pnas.0701311104

    Article  PubMed  CAS  Google Scholar 

  75. Kordower JH, Kanaan NM, Chu Y, Suresh Babu R, Stansell J 3rd, Terpstra BT, Sortwell CE, Steece-Collier K, Collier TJ (2006) Failure of proteasome inhibitor administration to provide a model of Parkinson’s disease in rats and monkeys. Ann Neurol 60(2):264–268. doi:10.1002/ana.20935

    Article  PubMed  CAS  Google Scholar 

  76. Korolchuk VI, Mansilla A, Menzies FM, Rubinsztein DC (2009) Autophagy inhibition compromises degradation of ubiquitin–proteasome pathway substrates. Mol Cell 33(4):517–527. doi:10.1016/j.molcel.2009.01.021

    Article  PubMed  CAS  Google Scholar 

  77. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N (2004) The role of autophagy during the early neonatal starvation period. Nature 432(7020):1032–1036. doi:10.1038/nature03029

    Article  PubMed  CAS  Google Scholar 

  78. Kuzuhara S, Mori H, Izumiyama N, Yoshimura M, Ihara Y (1988) Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study. Acta Neuropathol 75(4):345–353

    Article  PubMed  CAS  Google Scholar 

  79. Kwak S, Masaki T, Ishiura S, Sugita H (1991) Multicatalytic proteinase is present in Lewy bodies and neurofibrillary tangles in diffuse Lewy body disease brains. Neurosci Lett 128(1):21–24. doi:10.1016/0304-3940(91)90751-E

    Article  PubMed  CAS  Google Scholar 

  80. Lavedan C (1998) The synuclein family. Genome Res 8(9):871–880

    PubMed  CAS  Google Scholar 

  81. Lee BH, Lee MJ, Park S, Oh DC, Elsasser S, Chen PC, Gartner C, Dimova N, Hanna J, Gygi SP, Wilson SM, King RW, Finley D (2010) Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467(7312):179–184. doi:10.1038/nature09299

    Article  PubMed  CAS  Google Scholar 

  82. Lee HJ, Khoshaghideh F, Patel S, Lee SJ (2004) Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci 24(8):1888–1896. doi:10.1523/JNEUROSCI.3809-03.2004

    Article  PubMed  CAS  Google Scholar 

  83. Lee JT, Wheeler TC, Li L, Chin LS (2008) Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. Hum Mol Genet 17(6):906–917. doi:10.1093/hmg/ddm363

    Article  PubMed  CAS  Google Scholar 

  84. Lennox G, Lowe J, Morrell K, Landon M, Mayer RJ (1989) Anti-ubiquitin immunocytochemistry is more sensitive than conventional techniques in the detection of diffuse Lewy body disease. J Neurol Neurosurg Psychiatry 52(1):67–71

    Article  PubMed  CAS  Google Scholar 

  85. Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach PJ, Wilkinson KD, Polymeropoulos MH (1998) The ubiquitin pathway in Parkinson’s disease. Nature 395(6701):451–452. doi:10.1038/26652

    Article  PubMed  CAS  Google Scholar 

  86. Li L, Wang X, Fei X, Xia L, Qin Z, Liang Z (2011) Parkinson’s disease involves autophagy and abnormal distribution of cathepsin L. Neurosci Lett 489(1):62–67. doi:10.1016/j.neulet.2010.11.068

    Article  PubMed  CAS  Google Scholar 

  87. Liani E, Eyal A, Avraham E, Shemer R, Szargel R, Berg D, Bornemann A, Riess O, Ross CA, Rott R, Engelender S (2004) 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 101(15):5500–5505. doi:10.1073/pnas.0401081101

    Article  PubMed  CAS  Google Scholar 

  88. Lindersson E, Beedholm R, Hojrup P, Moos T, Gai W, Hendil KB, Jensen PH (2004) Proteasomal inhibition by alpha-synuclein filaments and oligomers. J Biol Chem 279(13):12924–12934. doi:10.1074/jbc.M306390200

    Article  PubMed  CAS  Google Scholar 

  89. Liu CW, Corboy MJ, DeMartino GN, Thomas PJ (2003) Endoproteolytic activity of the proteasome. Science 299(5605):408–411. doi:10.1126/science.1079293

    Article  PubMed  CAS  Google Scholar 

  90. Liu CW, Giasson BI, Lewis KA, Lee VM, Demartino GN, Thomas PJ (2005) A precipitating role for truncated alpha-synuclein and the proteasome in alpha-synuclein aggregation: implications for pathogenesis of Parkinson disease. J Biol Chem 280(24):22670–22678. doi:10.1074/jbc.M501508200

    Article  PubMed  CAS  Google Scholar 

  91. Liu K, Liu C, Shen L, Shi J, Zhang T, Zhou Y, Zhou L, Sun X (2011) Therapeutic effects of rapamycin on MPTP-induced Parkinsonism in mice. Neurochem Int. doi:10.1016/j.neuint.2011.05.011

  92. Lowe J, McDermott H, Landon M, Mayer RJ, Wilkinson KD (1990) Ubiquitin carboxyl-terminal hydrolase (PGP 9.5) is selectively present in ubiquitinated inclusion bodies characteristic of human neurodegenerative diseases. J Pathol 161(2):153–160. doi:10.1002/path.1711610210

    Article  PubMed  CAS  Google Scholar 

  93. Machiya Y, Hara S, Arawaka S, Fukushima S, Sato H, Sakamoto M, Koyama S, Kato T (2010) Phosphorylated alpha-synuclein at Ser-129 is targeted to the proteasome pathway in a ubiquitin-independent manner. J Biol Chem 285(52):40732–40744. doi:10.1074/jbc.M110.141952

    Article  PubMed  CAS  Google Scholar 

  94. MacInnes N, Iravani MM, Perry E, Piggott M, Perry R, Jenner P, Ballard C (2008) Proteasomal abnormalities in cortical Lewy body disease and the impact of proteasomal inhibition within cortical and cholinergic systems. J Neural Transm 115(6):869–878. doi:10.1007/s00702-008-0027-6

    Article  PubMed  CAS  Google Scholar 

  95. Mak SK, McCormack AL, Manning-Bog AB, Cuervo AM, Di Monte DA (2010) Lysosomal degradation of alpha-synuclein in vivo. J Biol Chem 285(18):13621–13629. doi:10.1074/jbc.M109.074617

    Article  PubMed  CAS  Google Scholar 

  96. Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA (2010) Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. J Neurosci 30(3):1166–1175. doi:10.1523/JNEUROSCI.3944-09.2010

    Article  PubMed  CAS  Google Scholar 

  97. Manning-Bog AB, Reaney SH, Chou VP, Johnston LC, McCormack AL, Johnston J, Langston JW, Di Monte DA (2006) Lack of nigrostriatal pathology in a rat model of proteasome inhibition. Ann Neurol 60(2):256–260. doi:10.1002/ana.20938

    Article  PubMed  Google Scholar 

  98. Marino G, Madeo F, Kroemer G (2011) Autophagy for tissue homeostasis and neuroprotection. Curr Opin Cell Biol 23(2):198–206. doi:10.1016/j.ceb.2010.10.001

    Article  PubMed  CAS  Google Scholar 

  99. Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury PT, Sulzer D, Cuervo AM (2008) Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Invest 118(2):777–788. doi:10.1172/JCI32806

    PubMed  CAS  Google Scholar 

  100. Massey AC, Kaushik S, Sovak G, Kiffin R, Cuervo AM (2006) Consequences of the selective blockage of chaperone-mediated autophagy. Proc Natl Acad Sci USA 103(15):5805–5810. doi:10.1073/pnas.0507436103

    Article  PubMed  CAS  Google Scholar 

  101. Mathur BN, Neely MD, Dyllick-Brenzinger M, Tandon A, Deutch AY (2007) Systemic administration of a proteasome inhibitor does not cause nigrostriatal dopamine degeneration. Brain Res 1168:83–89. doi:10.1016/j.brainres.2007.06.076

    Article  PubMed  CAS  Google Scholar 

  102. Matsui H, Ito H, Taniguchi Y, Inoue H, Takeda S, Takahashi R (2010) Proteasome inhibition in medaka brain induces the features of Parkinson’s disease. J Neurochem 115(1):178–187. doi:10.1111/j.1471-4159.2010.06918.x

    Article  PubMed  CAS  Google Scholar 

  103. Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D (2011) Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146(1):37–52. doi:10.1016/j.cell.2011.06.001

    Article  PubMed  CAS  Google Scholar 

  104. McLean PJ, Kawamata H, Hyman BT (2001) Alpha-synuclein-enhanced green fluorescent protein fusion proteins form proteasome sensitive inclusions in primary neurons. Neuroscience 104(3):901–912 pii:S0306-4522(01)00113-0

    Article  PubMed  CAS  Google Scholar 

  105. McNaught KS, Belizaire R, Isacson O, Jenner P, Olanow CW (2003) Altered proteasomal function in sporadic Parkinson’s disease. Exp Neurol 179(1):38–46

    Article  PubMed  CAS  Google Scholar 

  106. McNaught KS, Belizaire R, Jenner P, Olanow CW, Isacson O (2002) Selective loss of 20S proteasome alpha-subunits in the substantia nigra pars compacta in Parkinson’s disease. Neurosci Lett 326(3):155–158

    Article  PubMed  CAS  Google Scholar 

  107. McNaught KS, Jenner P (2001) Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci Lett 297(3):191–194

    Article  PubMed  CAS  Google Scholar 

  108. McNaught KS, Mytilineou C, Jnobaptiste R, Yabut J, Shashidharan P, Jennert P, Olanow CW (2002) Impairment of the ubiquitin–proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J Neurochem 81(2):301–306

    Article  PubMed  CAS  Google Scholar 

  109. McNaught KS, Olanow CW (2006) Proteasome inhibitor-induced model of Parkinson’s disease. Ann Neurol 60(2):243–247. doi:10.1002/ana.20936

    Article  PubMed  Google Scholar 

  110. Menzies FM, Hourez R, Imarisio S, Raspe M, Sadiq O, Chandraratna D, O’Kane C, Rock KL, Reits E, Goldberg AL, Rubinsztein DC (2010) Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy. Hum Mol Genet 19(23):4573–4586. doi:10.1093/hmg/ddq385

    Article  PubMed  CAS  Google Scholar 

  111. Meredith GE, Totterdell S, Petroske E, Santa Cruz K, Callison RC Jr, Lau YS (2002) Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson’s disease. Brain Res 956(1):156–165

    Article  PubMed  CAS  Google Scholar 

  112. Mijaljica D, Prescott M, Devenish RJ (2011) Microautophagy in mammalian cells: revisiting a 40-year-old conundrum. Autophagy 7(7):673–682

    Article  PubMed  CAS  Google Scholar 

  113. Miwa H, Kubo T, Suzuki A, Nishi K, Kondo T (2005) Retrograde dopaminergic neuron degeneration following intrastriatal proteasome inhibition. Neurosci Lett 380(1–2):93–98. doi:10.1016/j.neulet.2005.01.024

    Article  PubMed  CAS  Google Scholar 

  114. Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, Klionsky DJ, Ohsumi M, Ohsumi Y (1998) A protein conjugation system essential for autophagy. Nature 395(6700):395–398. doi:10.1038/26506

    Article  PubMed  CAS  Google Scholar 

  115. Noda T, Ohsumi Y (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273(7):3963–3966

    Article  PubMed  CAS  Google Scholar 

  116. Ohsumi Y (2001) Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol 2(3):211–216. doi:10.1038/35056522

    Article  PubMed  CAS  Google Scholar 

  117. Pan T, Kondo S, Zhu W, Xie W, Jankovic J, Le W (2008) Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol Dis 32(1):16–25. doi:10.1016/j.nbd.2008.06.003

    Article  PubMed  CAS  Google Scholar 

  118. Pan T, Rawal P, Wu Y, Xie W, Jankovic J, Le W (2009) Rapamycin protects against rotenone-induced apoptosis through autophagy induction. Neuroscience 164(2):541–551. doi:10.1016/j.neuroscience.2009.08.014

    Article  PubMed  CAS  Google Scholar 

  119. Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA, Knight MA, Schuldiner O, Padmanabhan R, Hild M, Berry DL, Garza D, Hubbert CC, Yao TP, Baehrecke EH, Taylor JP (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447(7146):859–863. doi:10.1038/nature05853

    Article  PubMed  CAS  Google Scholar 

  120. Paxinou E, Chen Q, Weisse M, Giasson BI, Norris EH, Rueter SM, Trojanowski JQ, Lee VM, Ischiropoulos H (2001) Induction of alpha-synuclein aggregation by intracellular nitrative insult. J Neurosci 21(20):8053–8061

    PubMed  CAS  Google Scholar 

  121. Petrucelli L, O’Farrell C, Lockhart PJ, Baptista M, Kehoe K, Vink L, Choi P, Wolozin B, Farrer M, Hardy J, Cookson MR (2002) Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36(6):1007–1019. pii:S089662730201125X

    Google Scholar 

  122. Prigione A, Piazza F, Brighina L, Begni B, Galbussera A, Difrancesco JC, Andreoni S, Piolti R, Ferrarese C (2010) Alpha-synuclein nitration and autophagy response are induced in peripheral blood cells from patients with Parkinson disease. Neurosci Lett 477(1):6–10. doi:10.1016/j.neulet.2010.04.022

    Article  PubMed  CAS  Google Scholar 

  123. Qiao L, Hamamichi S, Caldwell KA, Caldwell GA, Yacoubian TA, Wilson S, Xie ZL, Speake LD, Parks R, Crabtree D, Liang Q, Crimmins S, Schneider L, Uchiyama Y, Iwatsubo T, Zhou Y, Peng L, Lu Y, Standaert DG, Walls KC, Shacka JJ, Roth KA, Zhang J (2008) Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity. Mol Brain 1:17. doi:10.1186/1756-6606-1-17

    Article  PubMed  CAS  Google Scholar 

  124. Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP, Goebel I, Mubaidin AF, Wriekat AL, Roeper J, Al-Din A, Hillmer AM, Karsak M, Liss B, Woods CG, Behrens MI, Kubisch C (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38(10):1184–1191. doi:10.1038/ng1884

    Article  PubMed  CAS  Google Scholar 

  125. Rideout HJ, Dietrich P, Wang Q, Dauer WT, Stefanis L (2004) Alpha-synuclein is required for the fibrillar nature of ubiquitinated inclusions induced by proteasomal inhibition in primary neurons. J Biol Chem 279(45):46915–46920. doi:10.1074/jbc.M405146200

    Article  PubMed  CAS  Google Scholar 

  126. Rideout HJ, Lang-Rollin I, Stefanis L (2004) Involvement of macroautophagy in the dissolution of neuronal inclusions. Int J Biochem Cell Biol 36(12):2551–2562. doi:10.1016/j.biocel.2004.05.008

    Article  PubMed  CAS  Google Scholar 

  127. Rideout HJ, Larsen KE, Sulzer D, Stefanis L (2001) Proteasomal inhibition leads to formation of ubiquitin/alpha-synuclein-immunoreactive inclusions in PC12 cells. J Neurochem 78(4):899–908

    Article  PubMed  CAS  Google Scholar 

  128. Rideout HJ, Stefanis L (2002) Proteasomal inhibition-induced inclusion formation and death in cortical neurons require transcription and ubiquitination. Mol Cell Neurosci 21(2):223–238

    Article  PubMed  CAS  Google Scholar 

  129. Riedel M, Goldbaum O, Schwarz L, Schmitt S, Richter-Landsberg C (2010) 17-AAG induces cytoplasmic alpha-synuclein aggregate clearance by induction of autophagy. PLoS One 5(1):e8753. doi:10.1371/journal.pone.0008753

    Article  PubMed  CAS  Google Scholar 

  130. Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ (2007) Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6(4):304–312. doi:10.1038/nrd2272

    Article  PubMed  CAS  Google Scholar 

  131. Sardi SP, Clarke J, Kinnecom C, Tamsett TJ, Li L, Stanek LM, Passini MA, Grabowski GA, Schlossmacher MG, Sidman RL, Cheng SH, Shihabuddin LS (2011) CNS expression of glucocerebrosidase corrects {alpha}-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy. Proc Natl Acad Sci USA 108(29):12101–12106. doi:10.1073/pnas.1108197108

    Article  PubMed  CAS  Google Scholar 

  132. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC (2007) Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem 282(8):5641–5652. doi:10.1074/jbc.M609532200

    Article  PubMed  CAS  Google Scholar 

  133. Sarkar S, Krishna G, Imarisio S, Saiki S, O’Kane CJ, Rubinsztein DC (2008) A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum Mol Genet 17(2):170–178. doi:10.1093/hmg/ddm294

    Article  PubMed  CAS  Google Scholar 

  134. Sarkar S, Perlstein EO, Imarisio S, Pineau S, Cordenier A, Maglathlin RL, Webster JA, Lewis TA, O’Kane CJ, Schreiber SL, Rubinsztein DC (2007) Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat Chem Biol 3(6):331–338. doi:10.1038/nchembio883

    Article  PubMed  CAS  Google Scholar 

  135. Sawada H, Kohno R, Kihara T, Izumi Y, Sakka N, Ibi M, Nakanishi M, Nakamizo T, Yamakawa K, Shibasaki H, Yamamoto N, Akaike A, Inden M, Kitamura Y, Taniguchi T, Shimohama S (2004) Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes alpha-synuclein inclusions. J Biol Chem 279(11):10710–10719. doi:10.1074/jbc.M308434200

    Article  PubMed  CAS  Google Scholar 

  136. Schapira AH, Cleeter MW, Muddle JR, Workman JM, Cooper JM, King RH (2006) Proteasomal inhibition causes loss of nigral tyrosine hydroxylase neurons. Ann Neurol 60(2):253–255. doi:10.1002/ana.20934

    Article  PubMed  CAS  Google Scholar 

  137. Schlossmacher MG, Frosch MP, Gai WP, Medina M, Sharma N, Forno L, Ochiishi T, Shimura H, Sharon R, Hattori N, Langston JW, Mizuno Y, Hyman BT, Selkoe DJ, Kosik KS (2002) Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies. Am J Pathol 160(5):1655–1667. doi:10.1016/S0002-9440(10)61113-3

    Article  PubMed  CAS  Google Scholar 

  138. Sevlever D, Jiang P, Yen SH (2008) Cathepsin D is the main lysosomal enzyme involved in the degradation of alpha-synuclein and generation of its carboxy-terminally truncated species. Biochemistry 47(36):9678–9687. doi:10.1021/bi800699v

    Article  PubMed  CAS  Google Scholar 

  139. Shin Y, Klucken J, Patterson C, Hyman BT, McLean PJ (2005) The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways. J Biol Chem 280(25):23727–23734. doi:10.1074/jbc.M503326200

    Article  PubMed  CAS  Google Scholar 

  140. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 361(17):1651–1661. doi:10.1056/NEJMoa0901281

    Article  PubMed  CAS  Google Scholar 

  141. Smith MH, Ploegh HL, Weissman JS (2011) Road to ruin: targeting proteins for degradation in the endoplasmic reticulum. Science 334(6059):1086–1090. doi:10.1126/science.1209235

    Article  PubMed  CAS  Google Scholar 

  142. Snyder H, Mensah K, Theisler C, Lee J, Matouschek A, Wolozin B (2003) Aggregated and monomeric alpha-synuclein bind to the S6′ proteasomal protein and inhibit proteasomal function. J Biol Chem 278(14):11753–11759. doi:10.1074/jbc.M208641200

    Article  PubMed  CAS  Google Scholar 

  143. Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, Masliah E (2009) Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci 29(43):13578–13588. doi:10.1523/JNEUROSCI.4390-09.2009

    Article  PubMed  CAS  Google Scholar 

  144. Stefanis L, Larsen KE, Rideout HJ, Sulzer D, Greene LA (2001) Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci 21(24):9549–9560. pii:21/24/9549

    Google Scholar 

  145. Sun F, Anantharam V, Zhang D, Latchoumycandane C, Kanthasamy A, Kanthasamy AG (2006) Proteasome inhibitor MG-132 induces dopaminergic degeneration in cell culture and animal models. Neurotoxicology 27(5):807–815. doi:10.1016/j.neuro.2006.06.006

    Article  PubMed  CAS  Google Scholar 

  146. Tanaka Y, Engelender S, Igarashi S, Rao RK, Wanner T, Tanzi RE, Sawa A, Dawson LV, Dawson TM, Ross CA (2001) Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum Mol Genet 10(9):919–926

    Article  PubMed  CAS  Google Scholar 

  147. Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K (2011) Alteration of autophagosomal proteins (LC3, GABARAP and GATE-16) in Lewy body disease. Neurobiol Dis 43(3):690–697. doi:10.1016/j.nbd.2011.05.022

    Article  PubMed  CAS  Google Scholar 

  148. Tofaris GK, Kim HT, Hourez R, Jung JW, Kim KP, Goldberg AL (2011) Ubiquitin ligase Nedd4 promotes alpha-synuclein degradation by the endosomal–lysosomal pathway. Proc Natl Acad Sci USA 108(41):17004–17009. doi:10.1073/pnas.1109356108

    Article  PubMed  CAS  Google Scholar 

  149. Tofaris GK, Layfield R, Spillantini MG (2001) Alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett 509(1):22–26. pii:S0014-5793(01)03115-5

    Google Scholar 

  150. Tofaris GK, Razzaq A, Ghetti B, Lilley KS, Spillantini MG (2003) Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. J Biol Chem 278(45):44405–44411. doi:10.1074/jbc.M308041200

    Article  PubMed  CAS  Google Scholar 

  151. Tong Y, Giaime E, Yamaguchi H, Ichimura T, Liu Y, Si H, Cai H, Bonventre JV, Shen J (2012) Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Mol Neurodegener 7(1):2. doi:10.1186/1750-1326-7-2

    Article  PubMed  CAS  Google Scholar 

  152. Tong Y, Yamaguchi H, Giaime E, Boyle S, Kopan R, Kelleher RJ 3rd, Shen J (2010) Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice. Proc Natl Acad Sci USA 107(21):9879–9884. doi:10.1073/pnas.1004676107

    Article  PubMed  CAS  Google Scholar 

  153. Ullrich C, Mlekusch R, Kuschnig A, Marksteiner J, Humpel C (2010) Ubiquitin enzymes, ubiquitin and proteasome activity in blood mononuclear cells of MCI, Alzheimer and Parkinson patients. Curr Alzheimer Res 7(6):549–555

    Article  PubMed  CAS  Google Scholar 

  154. Um JW, Im E, Lee HJ, Min B, Yoo L, Yoo J, Lubbert H, Stichel-Gunkel C, Cho HS, Yoon JB, Chung KC (2010) Parkin directly modulates 26S proteasome activity. J Neurosci 30(35):11805–11814. doi:10.1523/JNEUROSCI.2862-09.2010

    Article  PubMed  CAS  Google Scholar 

  155. Unni VK, Ebrahimi-Fakhari D, Vanderburg CR, McLean PJ, Hyman BT (2011) Studying protein degradation pathways in vivo using a cranial window-based approach. Methods 53(3):194–200. doi:10.1016/j.ymeth.2010.12.032

    Article  PubMed  CAS  Google Scholar 

  156. Unni VK, Weissman TA, Rockenstein E, Masliah E, McLean PJ, Hyman BT (2010) In vivo imaging of alpha-synuclein in mouse cortex demonstrates stable expression and differential subcellular compartment mobility. PLoS One 5(5):e10589. doi:10.1371/journal.pone.0010589

    Article  PubMed  CAS  Google Scholar 

  157. Vernon AC, Johansson SM, Modo MM (2010) Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson’s disease. BMC Neurosci 11:1. doi:10.1186/1471-2202-11-1

    Article  PubMed  CAS  Google Scholar 

  158. Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L (2008) Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem 283(35):23542–23556. doi:10.1074/jbc.M801992200

    Article  PubMed  CAS  Google Scholar 

  159. Wang XF, Li S, Chou AP, Bronstein JM (2006) Inhibitory effects of pesticides on proteasome activity: implication in Parkinson’s disease. Neurobiol Dis 23(1):198–205. doi:10.1016/j.nbd.2006.02.012

    Article  PubMed  CAS  Google Scholar 

  160. Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278(27):25009–25013. doi:10.1074/jbc.M300227200

    Article  PubMed  CAS  Google Scholar 

  161. Williams A, Sarkar S, Cuddon P, Ttofi EK, Saiki S, Siddiqi FH, Jahreiss L, Fleming A, Pask D, Goldsmith P, O’Kane CJ, Floto RA, Rubinsztein DC (2008) Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway. Nat Chem Biol 4(5):295–305. doi:10.1038/nchembio.79

    Article  PubMed  CAS  Google Scholar 

  162. Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, Hetzer C, Loher T, Vilar M, Campioni S, Tzitzilonis C, Soragni A, Jessberger S, Mira H, Consiglio A, Pham E, Masliah E, Gage FH, Riek R (2011) In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci USA 108(10):4194–4199. doi:10.1073/pnas.1100976108

    Article  PubMed  CAS  Google Scholar 

  163. Winslow AR, Chen CW, Corrochano S, Acevedo-Arozena A, Gordon DE, Peden AA, Lichtenberg M, Menzies FM, Ravikumar B, Imarisio S, Brown S, O’Kane CJ, Rubinsztein DC (2010) Alpha-synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol 190(6):1023–1037. doi:10.1083/jcb.201003122

    Article  PubMed  CAS  Google Scholar 

  164. Wong AS, Lee RH, Cheung AY, Yeung PK, Chung SK, Cheung ZH, Ip NY (2011) Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson’s disease. Nat Cell Biol 13(5):568–579. doi:10.1038/ncb2217

    Article  PubMed  CAS  Google Scholar 

  165. Wong E, Cuervo AM (2010) Integration of clearance mechanisms: the proteasome and autophagy. Cold Spring Harb Perspect Biol 2(12):a006734. doi:10.1101/cshperspect.a006734

    Article  PubMed  CAS  Google Scholar 

  166. Wong ES, Tan JM, Soong WE, Hussein K, Nukina N, Dawson VL, Dawson TM, Cuervo AM, Lim KL (2008) Autophagy-mediated clearance of aggresomes is not a universal phenomenon. Hum Mol Genet 17(16):2570–2582. doi:10.1093/hmg/ddn157

    Article  PubMed  CAS  Google Scholar 

  167. Wu G, Wang X, Feng X, Zhang A, Li J, Gu K, Huang J, Pang S, Dong H, Gao H, Yan B (2011) Altered expression of autophagic genes in the peripheral leukocytes of patients with sporadic Parkinson’s disease. Brain Res 1394:105–111. doi:10.1016/j.brainres.2011.04.013

    Article  PubMed  CAS  Google Scholar 

  168. Xie W, Li X, Li C, Zhu W, Jankovic J, Le W (2010) Proteasome inhibition modeling nigral neuron degeneration in Parkinson’s disease. J Neurochem 115(1):188–199. doi:10.1111/j.1471-4159.2010.06914.x

    Article  PubMed  CAS  Google Scholar 

  169. Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L (2009) Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS One 4(5):e5515. doi:10.1371/journal.pone.0005515

    Article  PubMed  CAS  Google Scholar 

  170. Xiong N, Jia M, Chen C, Xiong J, Zhang Z, Huang J, Hou L, Yang H, Cao X, Liang Z, Sun S, Lin Z, Wang T (2011) Potential autophagy enhancers attenuate rotenone-induced toxicity in SH-SY5Y. Neuroscience 199:292–302. doi:10.1016/j.neuroscience.2011.10.031

    Article  PubMed  CAS  Google Scholar 

  171. Yamada S, Niwa J, Ishigaki S, Takahashi M, Ito T, Sone J, Doyu M, Sobue G (2006) Archaeal proteasomes effectively degrade aggregation-prone proteins and reduce cellular toxicities in mammalian cells. J Biol Chem 281(33):23842–23851. doi:10.1074/jbc.M601274200

    Article  PubMed  CAS  Google Scholar 

  172. Yang Q, She H, Gearing M, Colla E, Lee M, Shacka JJ, Mao Z (2009) Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science 323(5910):124–127. doi:10.1126/science.1166088

    Article  PubMed  CAS  Google Scholar 

  173. Yoshimoto Y, Nakaso K, Nakashima K (2005) l-dopa and dopamine enhance the formation of aggregates under proteasome inhibition in PC12 cells. FEBS Lett 579(5):1197–1202. doi:10.1016/j.febslet.2004.12.091

    Article  PubMed  CAS  Google Scholar 

  174. Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12(1):9–14. doi:10.1038/nrm3028

    Article  PubMed  CAS  Google Scholar 

  175. Yu WH, Dorado B, Figueroa HY, Wang L, Planel E, Cookson MR, Clark LN, Duff KE (2009) Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric alpha-synuclein. Am J Pathol 175(2):736–747. doi:10.2353/ajpath.2009.080928

    Article  PubMed  CAS  Google Scholar 

  176. Zeng BY, Bukhatwa S, Hikima A, Rose S, Jenner P (2006) Reproducible nigral cell loss after systemic proteasomal inhibitor administration to rats. Ann Neurol 60(2):248–252. doi:10.1002/ana.20932

    Article  PubMed  Google Scholar 

  177. Zeng BY, Iravani MM, Lin ST, Irifune M, Kuoppamaki M, Al-Barghouthy G, Smith L, Jackson MJ, Rose S, Medhurst AD, Jenner P (2006) MPTP treatment of common marmosets impairs proteasomal enzyme activity and decreases expression of structural and regulatory elements of the 26S proteasome. Eur J Neurosci 23(7):1766–1774. doi:10.1111/j.1460-9568.2006.04718.x

    Article  PubMed  Google Scholar 

  178. Zhang NY, Tang Z, Liu CW (2008) Alpha-synuclein protofibrils inhibit 26 S proteasome-mediated protein degradation: understanding the cytotoxicity of protein protofibrils in neurodegenerative disease pathogenesis. J Biol Chem 283(29):20288–20298. doi:10.1074/jbc.M710560200

    Article  PubMed  CAS  Google Scholar 

  179. Zhou Y, Gu G, Goodlett DR, Zhang T, Pan C, Montine TJ, Montine KS, Aebersold RH, Zhang J (2004) Analysis of alpha-synuclein-associated proteins by quantitative proteomics. J Biol Chem 279(37):39155–39164. doi:10.1074/jbc.M405456200

    Article  PubMed  CAS  Google Scholar 

  180. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12(1):21–35. doi:10.1038/nrm3025

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank the peer reviewers for their valuable and thoughtful comments, which have led to a substantial improvement of the manuscript. This work was supported by NIH NS063963 and NS073740 (P.J.M.), the German National Academic Foundation (Studienstiftung des deutschen Volkes to D.E.-F. and L.W.), the Hamburg Foundation for International Research and Studies (D.E.-F.) and the Parkinson’s Disease Foundation (D.E-F.).

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Authors and Affiliations

  1. MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA, 02129, USA

    Darius Ebrahimi-Fakhari, Lara Wahlster & Pamela J. McLean

  2. Institute of Anatomy and Cell Biology, Ruprecht-Karls University Heidelberg, INF 307, 69120, Heidelberg, Germany

    Darius Ebrahimi-Fakhari

  3. Institute of Physiology and Pathophysiology, Ruprecht-Karls University Heidelberg, INF 326, 69120, Heidelberg, Germany

    Lara Wahlster

  4. Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Pamela J. McLean

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  1. Darius Ebrahimi-Fakhari
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  2. Lara Wahlster
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  3. Pamela J. McLean
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Correspondence to Pamela J. McLean.

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Ebrahimi-Fakhari, D., Wahlster, L. & McLean, P.J. Protein degradation pathways in Parkinson’s disease: curse or blessing. Acta Neuropathol 124, 153–172 (2012). https://doi.org/10.1007/s00401-012-1004-6

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  • DOI: https://doi.org/10.1007/s00401-012-1004-6

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