Skip to main content

Advertisement

SpringerLink
Log in

Alpha-synuclein and Protein Degradation Systems: a Reciprocal Relationship

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

An increasing wealth of data indicates a close relationship between the presynaptic protein alpha-synuclein and Parkinson’s disease (PD) pathogenesis. Alpha-synuclein protein levels are considered as a major determinant of its neurotoxic potential, whereas secreted extracellular alpha-synuclein has emerged as an additional important factor in this regard. However, the manner of alpha-synuclein degradation in neurons remains contentious. Both the ubiquitin–proteasome system (UPS) and the autophagy–lysosome pathway (ALP)—mainly macroautophagy and chaperone-mediated autophagy—have been suggested to contribute to alpha-synuclein turnover. Additionally, other proteases such as calpains, neurosin, and metalloproteinases have been also proposed to have a role in intracellular and extracellular alpha-synuclein processing. Both UPS and ALP activity decline with aging and such decline may play a pivotal role in many neurodegenerative conditions. Alterations in these major proteolytic pathways may result in alpha-synuclein accumulation due to impaired clearance. Conversely, increased alpha-synuclein protein burden promotes the generation of aberrant species that may impair further UPS or ALP function, generating thus a bidirectional positive feedback loop leading to neuronal death. In the current review, we summarize the recent findings related to alpha-synuclein degradation, as well as to alpha-synuclein-mediated aberrant effects on protein degradation systems. Identifying the factors that regulate alpha-synuclein association to cellular proteolytic pathways may represent potential targets for therapeutic interventions in PD and related synucleinopathies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426:895–899

    Article  PubMed  CAS  Google Scholar 

  2. Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290:1717–1721

    Article  PubMed  CAS  Google Scholar 

  3. Dufty BM, Warner LR, Hou ST, Jiang SX, Gomez-Isla T, Leenhouts KM, Oxford JT, Feany MB, Masliah E, Rohn TT (2007) Calpain-cleavage of alpha-synuclein: connecting proteolytic processing to disease-linked aggregation. Am J Pathol 170:1725–1738

    Article  PubMed  CAS  Google Scholar 

  4. Mishizen-Eberz AJ, Guttmann RP, Giasson BI, Day GA 3rd, Hodara R, Ischiropoulos H, Lee VM, Trojanowski JQ, Lynch DR (2003) Distinct cleavage patterns of normal and pathologic forms of alpha-synuclein by calpain I in vitro. J Neurochem 86:836–847

    Article  PubMed  CAS  Google Scholar 

  5. Iwata A, Maruyama M, Akagi T, Hashikawa T, Kanazawa I, Tsuji S, Nukina N (2003) Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies. Hum Mol Genet 12:2625–2635

    Article  PubMed  CAS  Google Scholar 

  6. Kasai T, Tokuda T, Yamaguchi N, Watanabe Y, Kametani F, Nakagawa M, Mizuno T (2008) Cleavage of normal and pathological forms of alpha-synuclein by neurosin in vitro. Neurosci Lett 436:52–56

    Article  PubMed  CAS  Google Scholar 

  7. Sung JY, Park SM, Lee CH, Um JW, Lee HJ, Kim J, Oh YJ, Lee ST, Paik SR, Chung KC (2005) Proteolytic cleavage of extracellular secreted {alpha}-synuclein via matrix metalloproteinases. J Biol Chem 280:25216–25224

    Article  PubMed  CAS  Google Scholar 

  8. Levin J, Giese A, Boetzel K, Israel L, Hogen T, Nubling G, Kretzschmar H, Lorenzl S (2009) Increased alpha-synuclein aggregation following limited cleavage by certain matrix metalloproteinases. Exp Neurol 215:201–208

    Article  PubMed  CAS  Google Scholar 

  9. Tatebe H, Watanabe Y, Kasai T, Mizuno T, Nakagawa M, Tanaka M, Tokuda T (2010) Extracellular neurosin degrades alpha-synuclein in cultured cells. Neurosci Res 67:341–346

    Article  PubMed  CAS  Google Scholar 

  10. Glickman MH, Ciechanover A (2002) The ubiquitin–proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82:373–428

    PubMed  CAS  Google Scholar 

  11. Layfield R, Tooth D, Landon M, Dawson S, Mayer J, Alban A (2001) Purification of poly-ubiquitinated proteins by S5a-affinity chromatography. Proteomics 1:773–777

    Article  PubMed  CAS  Google Scholar 

  12. Gallastegui N, Groll M (2010) The 26S proteasome: assembly and function of a destructive machine. Trends Biochem Sci 35:634–642

    Article  PubMed  CAS  Google Scholar 

  13. Ardley HC, Robinson PA (2005) E3 ubiquitin ligases. Essays Biochem 41:15–30

    Article  PubMed  CAS  Google Scholar 

  14. Goldberg MS, Fleming SM, Palacino JJ, Cepeda C, Lam HA, Bhatnagar A, Meloni EG, Wu N, Ackerson LC, Klapstein GJ, Gajendiran M, Roth BL, Chesselet MF, Maidment NT, Levine MS, Shen J (2003) Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 278:43628–43635

    Article  PubMed  CAS  Google Scholar 

  15. Crews CM (2003) Feeding the machine: mechanisms of proteasome-catalyzed degradation of ubiquitinated proteins. Curr Opin Chem Biol 7:534–539

    Article  PubMed  CAS  Google Scholar 

  16. Benaroudj N, Zwickl P, Seemuller E, Baumeister W, Goldberg AL (2003) ATP hydrolysis by the proteasome regulatory complex PAN serves multiple functions in protein degradation. Mol Cell 11:69–78

    Article  PubMed  CAS  Google Scholar 

  17. Demartino GN, Gillette TG (2007) Proteasomes: machines for all reasons. Cell 129:659–662

    Article  PubMed  CAS  Google Scholar 

  18. Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477

    Article  PubMed  CAS  Google Scholar 

  19. Muller O, Sattler T, Flotenmeyer M, Schwarz H, Plattner H, Mayer A (2000) Autophagic tubes: vacuolar invaginations involved in lateral membrane sorting and inverse vesicle budding. J Cell Biol 151:519–528

    Article  PubMed  CAS  Google Scholar 

  20. Hollenbeck PJ (1993) Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport. J Cell Biol 121:305–315

    Article  PubMed  CAS  Google Scholar 

  21. Mehrpour M, Esclatine A, Beau I, Codogno P (2010) Overview of macroautophagy regulation in mammalian cells. Cell Res 20:748–762

    Article  PubMed  Google Scholar 

  22. Xilouri M, Stefanis L (2010) Autophagy in the central nervous system: implications for neurodegenerative disorders. CNS Neurol Disord Drug Targets 9:701–719

    Article  PubMed  CAS  Google Scholar 

  23. Ohsumi Y (2001) Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol 2:211–216

    Article  PubMed  CAS  Google Scholar 

  24. Klionsky DJ (2005) The molecular machinery of autophagy: unanswered questions. J Cell Sci 118:7–18

    Article  PubMed  CAS  Google Scholar 

  25. Jung CH, Ro SH, Cao J, Otto NM, Kim DH (2010) mTOR regulation of autophagy. FEBS Lett 584:1287–1295

    Article  PubMed  CAS  Google Scholar 

  26. Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, Massey DC, Menzies FM, Moreau K, Narayanan U, Renna M, Siddiqi FH, Underwood BR, Winslow AR, Rubinsztein DC (2010) Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 90:1383–1435

    Article  PubMed  CAS  Google Scholar 

  27. He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93

    Article  PubMed  CAS  Google Scholar 

  28. Ichimura Y, Kominami E, Tanaka K, Komatsu M (2008) Selective turnover of p62/A170/SQSTM1 by autophagy. Autophagy 4:1063–1066

    PubMed  CAS  Google Scholar 

  29. Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115:727–738

    Article  PubMed  CAS  Google Scholar 

  30. Thurston TL, Ryzhakov G, Bloor S, von Muhlinen N, Randow F (2009) The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat Immunol 10:1215–1221

    Article  PubMed  CAS  Google Scholar 

  31. Novak I, Kirkin V, McEwan DG, Zhang J, Wild P, Rozenknop A, Rogov V, Lohr F, Popovic D, Occhipinti A, Reichert AS, Terzic J, Dotsch V, Ney PA, Dikic I (2009) Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep 11:45–51

    Article  PubMed  CAS  Google Scholar 

  32. Kanki T, Wang K, Cao Y, Baba M, Klionsky DJ (2009) Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev Cell 17:98–109

    Article  PubMed  CAS  Google Scholar 

  33. Kirkin V, Lamark T, Sou YS, Bjorkoy G, Nunn JL, Bruun JA, Shvets E, McEwan DG, Clausen TH, Wild P, Bilusic I, Theurillat JP, Overvatn A, Ishii T, Elazar Z, Komatsu M, Dikic I, Johansen T (2009) A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell 33:505–516

    Article  PubMed  CAS  Google Scholar 

  34. Chiang HL, Terlecky SR, Plant CP, Dice JF (1989) A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. Science 246:382–385

    Article  PubMed  CAS  Google Scholar 

  35. Cuervo AM, Dice JF, Knecht E (1997) A population of rat liver lysosomes responsible for the selective uptake and degradation of cytosolic proteins. J Biol Chem 272:5606–5615

    Article  PubMed  CAS  Google Scholar 

  36. Cuervo AM, Dice JF (1996) A receptor for the selective uptake and degradation of proteins by lysosomes. Science 273:501–503

    Article  PubMed  CAS  Google Scholar 

  37. Agarraberes FA, Dice JF (2001) A molecular chaperone complex at the lysosomal membrane is required for protein translocation. J Cell Sci 114:2491–2499

    PubMed  CAS  Google Scholar 

  38. Bandyopadhyay U, Kaushik S, Varticovski L, Cuervo AM (2008) The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane. Mol Cell Biol 28:5747–5763

    Article  PubMed  CAS  Google Scholar 

  39. Hatem CL, Gough NR, Fambrough DM (1995) Multiple mRNAs encode the avian lysosomal membrane protein LAMP-2, resulting in alternative transmembrane and cytoplasmic domains. J Cell Sci 108(Pt 5):2093–2100

    PubMed  CAS  Google Scholar 

  40. Cuervo AM, Dice JF (2000) Regulation of lamp2a levels in the lysosomal membrane. Traffic 1:570–583

    Article  PubMed  CAS  Google Scholar 

  41. Cuervo AM, Knecht E, Terlecky SR, Dice JF (1995) Activation of a selective pathway of lysosomal proteolysis in rat liver by prolonged starvation. Am J Physiol 269:C1200–C1208

    PubMed  CAS  Google Scholar 

  42. Agarraberes FA, Terlecky SR, Dice JF (1997) An intralysosomal hsp70 is required for a selective pathway of lysosomal protein degradation. J Cell Biol 137:825–834

    Article  PubMed  CAS  Google Scholar 

  43. Martinez-Vicente M, Cuervo AM (2007) Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 6:352–361

    Article  PubMed  CAS  Google Scholar 

  44. 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 283:23542–23556

    Article  PubMed  CAS  Google Scholar 

  45. Massey AC, Kaushik S, Sovak G, Kiffin R, Cuervo AM (2006) Consequences of the selective blockage of chaperone-mediated autophagy. Proc Natl Acad Sci U S A 103:5805–5810

    Article  PubMed  CAS  Google Scholar 

  46. Wang Y., Singh R., Massey A.C., Kane S.S., Kaushik S., Grant T., Xiang Y., Cuervo A.M., and Czaja M.J. (2007) Loss of macroautophagy promotes or prevents fibroblast apoptosis depending on the death stimulus. J Biol Chem

  47. Kaushik S, Massey AC, Mizushima N, Cuervo AM (2008) Constitutive activation of chaperone-mediated autophagy in cells with impaired macroautophagy. Mol Biol Cell 19:2179–2192

    Article  PubMed  CAS  Google Scholar 

  48. Cuervo AM, Dice JF (2000) Age-related decline in chaperone-mediated autophagy. J Biol Chem 275:31505–31513

    Article  PubMed  CAS  Google Scholar 

  49. Cuervo AM, Dice JF (2000) Unique properties of lamp2a compared to other lamp2 isoforms. J Cell Sci 113(Pt 24):4441–4450

    PubMed  CAS  Google Scholar 

  50. Zhang C, Cuervo AM (2008) Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 14:959–965

    Article  PubMed  CAS  Google Scholar 

  51. Liu CW, Corboy MJ, DeMartino GN, Thomas PJ (2003) Endoproteolytic activity of the proteasome. Science 299:408–411

    Article  PubMed  CAS  Google Scholar 

  52. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295

    Article  PubMed  CAS  Google Scholar 

  53. Leroy E, Anastasopoulos D, Konitsiotis S, Lavedan C, Polymeropoulos MH (1998) Deletions in the Parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson's disease. Hum Genet 103:424–427

    Article  PubMed  CAS  Google Scholar 

  54. 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 395:451–452

    Article  PubMed  CAS  Google Scholar 

  55. Maraganore DM, Lesnick TG, Elbaz A, Chartier-Harlin MC, Gasser T, Kruger R, Hattori N, Mellick GD, Quattrone A, Satoh J, Toda T, Wang J, Ioannidis JP, de Andrade M, Rocca WA (2004) UCHL1 is a Parkinson's disease susceptibility gene. Ann Neurol 55:512–521

    Article  PubMed  CAS  Google Scholar 

  56. 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 392:605–608

    Article  PubMed  CAS  Google Scholar 

  57. Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, Mizuno Y, Kosik KS, Selkoe DJ (2001) Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293:263–269

    Article  PubMed  CAS  Google Scholar 

  58. Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT Jr (2002) The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell 111:209–218

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  60. Imai Y, Soda M, Takahashi R (2000) Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem 275:35661–35664

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  63. Tofaris GK, Layfield R, Spillantini MG (2001) Alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett 509:22–26

    Article  PubMed  CAS  Google Scholar 

  64. Nakajima T, Takauchi S, Ohara K, Kokai M, Nishii R, Maeda S, Takanaga A, Tanaka T, Takeda M, Seki M, Morita Y (2005) Alpha-synuclein-positive structures induced in leupeptin-infused rats. Brain Res 1040:73–80

    Article  PubMed  CAS  Google Scholar 

  65. 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 285:40732–40744

    Article  PubMed  CAS  Google Scholar 

  66. 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 285:79–82

    Article  PubMed  CAS  Google Scholar 

  67. 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 78:899–908

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  69. Emmanouilidou E, Stefanis L, Vekrellis K (2010) Cell-produced alpha-synuclein oligomers are targeted to, and impair, the 26S proteasome. Neurobiol Aging 31:953–968

    Article  PubMed  CAS  Google Scholar 

  70. Lee HJ, Khoshaghideh F, Patel S, Lee SJ (2004) Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci 24:1888–1896

    Article  PubMed  CAS  Google Scholar 

  71. 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 280:23727–23734

    Article  PubMed  CAS  Google Scholar 

  72. 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 U S A 101:5500–5505

    Article  PubMed  CAS  Google Scholar 

  73. 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 17:906–917

    Article  PubMed  CAS  Google Scholar 

  74. Rott R, Szargel R, Haskin J, Bandopadhyay R, Lees AJ, Shani V, Engelender S (2011) alpha-Synuclein fate is determined by USP9X-regulated monoubiquitination. Proc Natl Acad Sci U S A 108:18666–18671

    Article  PubMed  CAS  Google Scholar 

  75. 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 U S A 108:17004–17009

    Article  PubMed  CAS  Google Scholar 

  76. 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 28:8189–8198

    Article  PubMed  CAS  Google Scholar 

  77. 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 279:46915–46920

    Article  PubMed  CAS  Google Scholar 

  78. 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 31:14508–14520

    Article  PubMed  CAS  Google Scholar 

  79. Alvarez-Erviti L., Rodriguez-Oroz M.C., Cooper J.M., Caballero C., Ferrer I., Obeso J.A., and Schapira A.H. (2010) Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol

  80. 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 21:8053–8061

    PubMed  CAS  Google Scholar 

  81. 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 29:13578–13588

    Article  PubMed  CAS  Google Scholar 

  82. Dice JF, Chiang HL, Spencer EP, Backer JM (1986) Regulation of catabolism of microinjected ribonuclease A. Identification of residues 7–11 as the essential pentapeptide. J Biol Chem 261:6853–6859

    PubMed  CAS  Google Scholar 

  83. Mak SK, McCormack AL, Manning-Bog AB, Cuervo AM, Di Monte DA (2010) Lysosomal degradation of alpha-synuclein in vivo. J Biol Chem 285:13621–13629

    Article  PubMed  CAS  Google Scholar 

  84. 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 47:9678–9687

    Article  PubMed  CAS  Google Scholar 

  85. Qiao L., Hamamichi S., Caldwell K.A., Caldwell G.A., Yacoubian T.A., Wilson S., Xie Z.L., Speake L.D., Parks R., Crabtree D., Liang Q., Crimmins S., Schneider L., Uchiyama Y., Iwatsubo T., Zhou Y., Peng L., Lu Y., Standaert D.G., Walls K.C., Shacka J.J., Roth K.A., and Zhang J. (2008) Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity. Mol Brain 1: p. 17

    Google Scholar 

  86. Cullen V, Lindfors M, Ng J, Paetau A, Swinton E, Kolodziej P, Boston H, Saftig P, Woulfe J, Feany MB, Myllykangas L, Schlossmacher MG, Tyynela J (2009) Cathepsin D expression level affects alpha-synuclein processing, aggregation, and toxicity in vivo. Mol Brain 2:5

    Article  PubMed  CAS  Google Scholar 

  87. Bartels T, Choi JG, Selkoe DJ (2011) alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477:107–110

    Article  PubMed  CAS  Google Scholar 

  88. Wang W, Perovic I, Chittuluru J, Kaganovich A, Nguyen LT, Liao J, Auclair JR, Johnson D, Landeru A, Simorellis AK, Ju S, Cookson MR, Asturias FJ, Agar JN, Webb BN, Kang C, Ringe D, Petsko GA, Pochapsky TC, Hoang QQ (2011) A soluble alpha-synuclein construct forms a dynamic tetramer. Proc Natl Acad Sci U S A 108:17797–17802

    Article  PubMed  CAS  Google Scholar 

  89. Choi DH, Kim YJ, Kim YG, Joh TH, Beal MF, Kim YS (2011) Role of matrix metalloproteinase 3-mediated alpha-synuclein cleavage in dopaminergic cell death. J Biol Chem 286:14168–14177

    Article  PubMed  CAS  Google Scholar 

  90. Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T (1998) Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J Pathol 152:879–884

    PubMed  CAS  Google Scholar 

  91. 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 280:22670–22678

    Article  PubMed  CAS  Google Scholar 

  92. Masliah E, Rockenstein E, Mante M, Crews L, Spencer B, Adame A, Patrick C, Trejo M, Ubhi K, Rohn TT, Mueller-Steiner S, Seubert P, Barbour R, McConlogue L, Buttini M, Games D, Schenk D (2011) Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One 6:e19338

    Article  PubMed  CAS  Google Scholar 

  93. Ogawa K, Yamada T, Tsujioka Y, Taguchi J, Takahashi M, Tsuboi Y, Fujino Y, Nakajima M, Yamamoto T, Akatsu H, Mitsui S, Yamaguchi N (2000) Localization of a novel type trypsin-like serine protease, neurosin, in brain tissues of Alzheimer's disease and Parkinson's disease. Psychiatry Clin Neurosci 54:419–426

    Article  PubMed  CAS  Google Scholar 

  94. Petraki CD, Karavana VN, Skoufogiannis PT, Little SP, Howarth DJ, Yousef GM, Diamandis EP (2001) The spectrum of human kallikrein 6 (zyme/protease M/neurosin) expression in human tissues as assessed by immunohistochemistry. J Histochem Cytochem 49:1431–1441

    Article  PubMed  CAS  Google Scholar 

  95. Okui A, Kominami K, Uemura H, Mitsui S, Yamaguchi N (2001) Characterization of a brain-related serine protease, neurosin (human kaillikrein 6), in human cerebrospinal fluid. Neuroreport 12:1345–1350

    Article  PubMed  CAS  Google Scholar 

  96. Diamandis EP, Yousef GM, Soosaipillai AR, Grass L, Porter A, Little S, Sotiropoulou G (2000) Immunofluorometric assay of human kallikrein 6 (zyme/protease M/neurosin) and preliminary clinical applications. Clin Biochem 33:369–375

    Article  PubMed  CAS  Google Scholar 

  97. Yong VW (2005) Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci 6:931–944

    Article  PubMed  CAS  Google Scholar 

  98. Choi DH, Kim EM, Son HJ, Joh TH, Kim YS, Kim D, Flint Beal M, Hwang O (2008) A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells. J Neurochem 106:405–415

    Article  PubMed  CAS  Google Scholar 

  99. Choi DH, Hwang O, Lee KH, Lee J, Beal MF, Kim YS (2010) DJ-1 cleavage by matrix metalloproteinase 3 mediates oxidative stress-induced dopaminergic cell death. Antioxid Redox Signal 14:2137–2150

    Article  CAS  Google Scholar 

  100. Joo SH, Kwon KJ, Kim JW, Hasan MR, Lee HJ, Han SH, Shin CY (2009) Regulation of matrix metalloproteinase-9 and tissue plasminogen activator activity by alpha-synuclein in rat primary glial cells. Neurosci Lett 469:352–356

    Article  PubMed  CAS  Google Scholar 

  101. Lee EJ, Woo MS, Moon PG, Baek MC, Choi IY, Kim WK, Junn E, Kim HS (2010) Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1. J Immunol 185:615–623

    Article  PubMed  CAS  Google Scholar 

  102. 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 441:885–889

    Article  PubMed  CAS  Google Scholar 

  103. 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 441:880–884

    Article  PubMed  CAS  Google Scholar 

  104. 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 131:1149–1163

    Article  PubMed  CAS  Google Scholar 

  105. Xilouri M, Stefanis L (2011) Autophagic pathways in Parkinson disease and related disorders. Expert Rev Mol Med 13:e8

    Article  PubMed  CAS  Google Scholar 

  106. Chu Y, Kordower JH (2007) Age-associated increases of alpha-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: is this the target for Parkinson's disease? Neurobiol Dis 25:134–149

    Article  PubMed  CAS  Google Scholar 

  107. Ward WF (2002) Protein degradation in the aging organism. Prog Mol Subcell Biol 29:35–42

    Article  PubMed  CAS  Google Scholar 

  108. 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 21:9549–9560

    PubMed  CAS  Google Scholar 

  109. 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 36:1007–1019

    Article  PubMed  CAS  Google Scholar 

  110. Tanaka Y., Engelender S., Igarashi S., Rao R.K., Wanner T., Tanzi R.E., Sawa A., V L.D., Dawson T.M., and Ross C.A. (2001) Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum Mol Genet 10:919–926

  111. 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 278:11753–11759

    Article  PubMed  CAS  Google Scholar 

  112. Smith WW, Jiang H, Pei Z, Tanaka Y, Morita H, Sawa A, Dawson VL, Dawson TM, Ross CA (2005) Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity. Hum Mol Genet 14:3801–3811

    Article  PubMed  CAS  Google Scholar 

  113. 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 279:12924–12934

    Article  PubMed  CAS  Google Scholar 

  114. Ghee M, Fournier A, Mallet J (2000) Rat alpha-synuclein interacts with Tat binding protein 1, a component of the 26S proteasomal complex. J Neurochem 75:2221–2224

    Article  PubMed  CAS  Google Scholar 

  115. Chen Q, Thorpe J, Keller JN (2005) Alpha-synuclein alters proteasome function, protein synthesis, and stationary phase viability. J Biol Chem 280:30009–30017

    Article  PubMed  CAS  Google Scholar 

  116. Martin-Clemente B, Alvarez-Castelao B, Mayo I, Sierra AB, Diaz V, Milan M, Farinas I, Gomez-Isla T, Ferrer I, Castano JG (2004) Alpha-synuclein expression levels do not significantly affect proteasome function and expression in mice and stably transfected PC12 cell lines. J Biol Chem 279:52984–52990

    Article  PubMed  CAS  Google Scholar 

  117. Emmanouilidou E., Stefanis L., and Vekrellis K. (2010) Cell-produced alpha-synuclein oligomers are targeted to, and impair, the 26S proteasome. Neurobiol Aging

  118. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521–533

    Article  PubMed  CAS  Google Scholar 

  119. Pickart CM, Cohen RE (2004) Proteasomes and their kin: proteases in the machine age. Nat Rev Mol Cell Biol 5:177–187

    Article  PubMed  CAS  Google Scholar 

  120. Kristiansen M, Deriziotis P, Dimcheff DE, Jackson GS, Ovaa H, Naumann H, Clarke AR, van Leeuwen FW, Menendez-Benito V, Dantuma NP, Portis JL, Collinge J, Tabrizi SJ (2007) Disease-associated prion protein oligomers inhibit the 26S proteasome. Mol Cell 26:175–188

    Article  PubMed  CAS  Google Scholar 

  121. Cuervo AM, Wong ES, Martinez-Vicente M (2010) Protein degradation, aggregation, and misfolding. Mov Disord 25(Suppl 1):S49–S54

    Article  PubMed  Google Scholar 

  122. 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 175:736–747

    Article  PubMed  CAS  Google Scholar 

  123. 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:e9313

    Article  PubMed  CAS  Google Scholar 

  124. Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L (2009) Aberrant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS One 4:e5515

    Article  PubMed  CAS  Google Scholar 

  125. 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 118:777–788

    PubMed  CAS  Google Scholar 

  126. Collier TJ, Kanaan NM, Kordower JH (2011) Ageing as a primary risk factor for Parkinson's disease: evidence from studies of non-human primates. Nat Rev Neurosci 12:359–366

    Article  PubMed  CAS  Google Scholar 

  127. 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 286:10814–10824

    Article  PubMed  CAS  Google Scholar 

  128. 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 190:1023–1037

    Article  PubMed  CAS  Google Scholar 

  129. 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 323:124–127

    Article  PubMed  CAS  Google Scholar 

  130. 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 361:1651–1661

    Article  PubMed  CAS  Google Scholar 

  131. Manning-Bog AB, Schule B, Langston JW (2009) Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: a biological link between Gaucher disease and parkinsonism. Neurotoxicology 30:1127–1132

    Article  PubMed  CAS  Google Scholar 

  132. 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

    Article  PubMed  CAS  Google Scholar 

  133. 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 U S A 108:12101–12106

    Article  PubMed  CAS  Google Scholar 

  134. Yap TL, Gruschus JM, Velayati A, Westbroek W, Goldin E, Moaven N, Sidransky E, Lee JC (2011) {alpha}-Synuclein interacts with glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases. J Biol Chem 286:28080–28088

    Article  PubMed  CAS  Google Scholar 

  135. 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 69:940–953

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens (BRFAA), 4 Soranou Efesiou Street, Athens, 11527, Greece

    Maria Xilouri, Oystein Rod Brekk & Leonidas Stefanis

  2. Second Department of Neurology, University of Athens Medical School, Athens, Greece

    Leonidas Stefanis

Authors
  1. Maria Xilouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oystein Rod Brekk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leonidas Stefanis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Xilouri.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xilouri, M., Brekk, O.R. & Stefanis, L. Alpha-synuclein and Protein Degradation Systems: a Reciprocal Relationship. Mol Neurobiol 47, 537–551 (2013). https://doi.org/10.1007/s12035-012-8341-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-012-8341-2

Keywords

Search

Navigation