Inhibition of α-Synuclein Aggregation by Antioxidants and Chaperones in Parkinson’s Disease

  • Jean-Christophe Rochet
  • Fang Liu
Part of the Focus on Structural Biology book series (FOSB, volume 7)


Parkinson’s disease (PD) is a neurodegenerative disorder involving a loss of dopaminergic neurons from the substantia nigra. A characteristic feature of the post-mortem brains of PD patients is the presence in surviving neurons of Lewy bodies, cytosolic inclusions enriched with fibrillar forms of the presynaptic protein α-synuclein. Upon prolonged incubation at physiological temperature, α-synuclein converts from a natively unfolded protein to β-sheet-rich fibrils. α-Synuclein fibrillization involves a transient buildup of ‘protofibrils’, prefibrillar oligomers that may elicit neurotoxicity by permeabilizing phospholipid membranes and/or by interfering with cellular protein clearance mechanisms. The formation of α-synuclein protofibrils is stimulated by post-translational modifications (e.g. tyrosine nitration, dopamine adduct formation, methionine oxidation) that occur readily under conditions of oxidative stress. α-Synuclein self-assembly is inhibited by the antioxidant repair enzyme methionine sulfoxide reductase A, antioxidant compounds, and various proteins with molecular chaperone activity. The upregulation of antioxidant- and chaperone-dependent mechanisms may be a reasonable therapeutic strategy for suppressing α-synuclein aggregation and toxicity in PD.


Multiple System Atrophy Rosmarinic Acid Methionine Sulfoxide Reductase Dopaminergic Cell Death Primary Midbrain Culture 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822.PubMedGoogle Scholar
  2. 2.
    Greenamyre JT, Sherer TB, Betarbet R, Panov AV (2001) Complex I and Parkinson’s disease. IUBMB Life 52:135–141.PubMedGoogle Scholar
  3. 3.
    Orth M, Schapira AH (2002) Mitochondrial involvement in Parkinson’s disease. Neurochem Int 40:533–541.PubMedGoogle Scholar
  4. 4.
    Beal MF (2003) Mitochondria, oxidative damage, and inflammation in Parkinson’s disease. Ann N Y Acad Sci 991:120–131.PubMedGoogle Scholar
  5. 5.
    Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53 Suppl 3:S26–S36; discussion S36–S28.PubMedGoogle Scholar
  6. 6.
    Graham DG, Tiffany SM, Bell WR Jr, Gutknecht WF (1978) Autoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds toward C1300 neuroblastoma cells in vitro. Mol Pharmacol 14:644–653.PubMedGoogle Scholar
  7. 7.
    Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA, Kittel A, Saitoh T (1995) The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14:467–475.PubMedGoogle Scholar
  8. 8.
    Spillantini MG, Schmidt ML, Lee VM-Y, Trojanowski JQ, Jakes R, Goedert M (1997) α-Synuclein in Lewy bodies. Nature 388:839–840.PubMedGoogle Scholar
  9. 9.
    Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047.PubMedGoogle Scholar
  10. 10.
    Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108.PubMedGoogle Scholar
  11. 11.
    Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B et al (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173.PubMedGoogle Scholar
  12. 12.
    Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R et al (2003) Alpha-synuclein locus triplication causes Parkinson’s disease. Science 302:841.PubMedGoogle Scholar
  13. 13.
    Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S, Levecque C, Larvor L, Andrieux J, Hulihan M et al (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364:1167–1169.PubMedGoogle Scholar
  14. 14.
    Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DAC, Kondo J, Ihara Y, Saitoh T (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 90:11282–11286.PubMedGoogle Scholar
  15. 15.
    Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815.PubMedGoogle Scholar
  16. 16.
    Fortin DL, Troyer MD, Nakamura K, Kubo S, Anthony MD, Edwards RH (2004) Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci 24:6715–6723.PubMedGoogle Scholar
  17. 17.
    Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A et al (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252.PubMedGoogle Scholar
  18. 18.
    Murphy DD, Rueter SM, Trojanowski JQ, Lee VM (2000) Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 20:3214–3220.PubMedGoogle Scholar
  19. 19.
    Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R et al (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking α-synuclein. J Neurosci 22:8797–8807.PubMedGoogle Scholar
  20. 20.
    Sidhu A, Wersinger C, Moussa CE, Vernier P (2004) The role of alpha-synuclein in both neuroprotection and neurodegeneration. Ann N Y Acad Sci 1035:250–270.PubMedGoogle Scholar
  21. 21.
    Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC (2005) Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123:383–396.PubMedGoogle Scholar
  22. 22.
    Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT Jr (1996) NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 35:13709–13715.PubMedGoogle Scholar
  23. 23.
    Eliezer D, Kutluay E, Bussell R Jr, Browne G (2001) Conformational properties of α-synuclein in its free and lipid-associated states. J Mol Biol 307:1061–1073.PubMedGoogle Scholar
  24. 24.
    Davidson WS, Jonas A, Clayton DF, George JM (1998) Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem 273:9443–9449.PubMedGoogle Scholar
  25. 25.
    Bussell R Jr, Eliezer D (2003) A structural and functional role for 11-mer repeats in α-synuclein and other exchangeable lipid binding proteins. J Mol Biol 329:763–778.PubMedGoogle Scholar
  26. 26.
    Chandra S, Chen X, Rizo J, Jahn R, Sudhof TC (2003) A broken α-helix in folded α-synuclein. J Biol Chem 278:15313–15318.PubMedGoogle Scholar
  27. 27.
    Jao CC, Der-Sarkissian A, Chen J, Langen R (2004) Structure of membrane-bound alpha-synuclein studied by site-directed spin labeling. Proc Natl Acad Sci USA 101:8331–8336.PubMedGoogle Scholar
  28. 28.
    Narhi L, Wood SJ, Steavenson S, Jiang Y, Wu GM, Anafi D, Kaufman SA, Martin F, Sitney K, Denis P et al (1999) Both familial Parkinson’s disease mutations accelerate alpha-synuclein aggregation. J Biol Chem 274:9843–9846.PubMedGoogle Scholar
  29. 29.
    Conway KA, Harper JD, Lansbury PT Jr (2000) Fibrils formed in vitro from α-synuclein and two mutant forms linked to Parkinson’s disease are typical amyloid. Biochemistry 39:2552–2563.PubMedGoogle Scholar
  30. 30.
    El-Agnaf OM, Jakes R, Curran MD, Wallace A (1998) Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of alpha-synuclein protein implicated in Parkinson’s disease. FEBS Lett 440:67–70.PubMedGoogle Scholar
  31. 31.
    Rochet JC, Conway KA, Lansbury PT Jr (2000) Inhibition of fibrillization and accumulation of prefibrillar oligomers in mixtures of human and mouse alpha-synuclein. Biochemistry 39:10619–10626.PubMedGoogle Scholar
  32. 32.
    Serpell LC, Berriman J, Jakes R, Goedert M, Crowther RA (2000) Fiber diffraction of synthetic α-synuclein filaments shows amyloid-like cross-β conformation. Proc Natl Acad Sci USA 97:4897–4902.PubMedGoogle Scholar
  33. 33.
    Conway KA, Harper JD, Lansbury PT (1998) Accelerated in vitro fibril formation by a mutant α–synuclein linked to early-onset Parkinson disease. Nat Med 4:1318–1320.PubMedGoogle Scholar
  34. 34.
    Giasson BI, Uryu K, Trojanowski JQ Lee VM-Y (1999) Mutant and wild type human α-synucleins assemble into elongated filaments with distinct morphologies in vitro. J Biol Chem 274:7619–7622.PubMedGoogle Scholar
  35. 35.
    Conway KA, Lee S-J, Rochet J-C, Ding TT, Williamson RE, Lansbury PT Jr (2000) Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson’s disease: Implications for pathogenesis and therapy. Proc Natl Acad Sci USA 97:571–576.PubMedGoogle Scholar
  36. 36.
    Choi W, Zibaee S, Jakes R, Serpell LC, Davletov B, Crowther RA, Goedert M (2004) Mutation E46K increases phospholipid binding and assembly into filaments of human alpha-synuclein. FEBS Lett 576:363–368.PubMedGoogle Scholar
  37. 37.
    Greenbaum EA, Graves CL, Mishizen-Eberz AJ, Lupoli MA, Lynch DR, Englander SW, Axelsen PH, Giasson BI (2005) The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem 280:7800–7807.PubMedGoogle Scholar
  38. 38.
    Fredenburg RA, Rospigliosi C, Meray RK, Kessler JC, Lashuel HA, Eliezer D, Lansbury PT Jr (2007) The impact of the E46K mutation on the properties of alpha-synuclein in its monomeric and oligomeric states. Biochemistry 46:7107–7118.PubMedGoogle Scholar
  39. 39.
    Volles MJ, Lee S-J, Rochet J-C, Shtilerman MD, Ding TT, Kessler JC, Lansbury PT Jr (2001) Vesicle permeabilization by protofibrillar α-synuclein: implications for the pathogenesis and treatment of Parkinson’s disease. Biochemistry 40:7812–7819.PubMedGoogle Scholar
  40. 40.
    Ding TT, Lee S-J, Rochet J-C, Lansbury PT Jr (2002) Annular α-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranes. Biochemistry 41:10209–10217.PubMedGoogle Scholar
  41. 41.
    Lashuel HA, Petre BM, Wall J, Simon M, Nowak RJ, Walz T, Lansbury PT Jr (2002) α-Synuclein, especially the Parkinson’s disease-associated mutants, forms pore-like annular and tubular protofibrils. J Mol Biol 322:1089–1102.PubMedGoogle Scholar
  42. 42.
    Volles MJ, Lansbury PT Jr (2003) Zeroing in on the pathogenic form of α-synuclein and its mechanism of neurotoxicity in Parkinson’s disease. Biochemistry 42:7871–7878.PubMedGoogle Scholar
  43. 43.
    Rochet JC, Outeiro TF, Conway KA, Ding TT, Volles MJ, Lashuel HA, Bieganski RM, Lindquist SL, Lansbury PT (2004) Interactions among alpha-synuclein, dopamine, and biomembranes: some clues for understanding neurodegeneration in Parkinson’s disease. J Mol Neurosci 23:23–34.PubMedGoogle Scholar
  44. 44.
    Li J, Uversky VN, Fink AL (2001) Effect of familial Parkinson’s disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human α-synuclein. Biochemistry 40:11604–11613.PubMedGoogle Scholar
  45. 45.
    Volles MJ, Lansbury PT Jr (2002) Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson’s disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 41:4595–4602.PubMedGoogle Scholar
  46. 46.
    Kayed R, Sokolov Y, Edmonds B, McIntire TM, Milton SC, Hall JE, Glabe CG (2004) Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J Biol Chem 279:46363–46366.PubMedGoogle Scholar
  47. 47.
    Quist A, Doudevski I, Lin H, Azimova R, Ng D, Frangione B, Kagan B, Ghiso J, Lal R (2005) Amyloid ion channels: a common structural link for protein-misfolding disease. Proc Natl Acad Sci USA 102:10427–10432.PubMedGoogle Scholar
  48. 48.
    Zakharov SD, Hulleman JD, Dutseva EA, Antonenko YN, Rochet JC, Cramer WA (2007) Helical alpha-synuclein forms highly conductive ion channels. Biochemistry 46:14369–14379.PubMedGoogle Scholar
  49. 49.
    Lee H-J, Choi C, Lee S-J (2002) Membrane-bound α-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form. J Biol Chem 277:671–678.PubMedGoogle Scholar
  50. 50.
    Perrin RJ, Woods WS, Clayton DF George JM (2001) Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins. J Biol Chem 276:41958–41962.PubMedGoogle Scholar
  51. 51.
    Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA Selkoe DJ (2003) The formation of highly soluble oligomers of α-synuclein is regulated by fatty acids and enhanced in Parkinson’s disease. Neuron 37:583–595.PubMedGoogle Scholar
  52. 52.
    Jo E, Darabie AA, Han K, Tandon A, Fraser PE, McLaurin J (2004) Alpha-synuclein-synaptosomal membrane interactions: implications for fibrillogenesis. Eur J Biochem 271:3180–3189.PubMedGoogle Scholar
  53. 53.
    Narayanan V, Scarlata S (2001) Membrane binding and self-association of alpha-synucleins. Biochemistry 40:9927–9934.PubMedGoogle Scholar
  54. 54.
    Necula M, Chirita CN, Kuret J (2003) Rapid anionic micelle-mediated alpha-synuclein fibrillization in vitro. J Biol Chem 278:46674–46680.PubMedGoogle Scholar
  55. 55.
    Zhu M, Fink AL (2003) Lipid binding inhibits α-synuclein fibril formation. J Biol Chem 278:16873–16877.PubMedGoogle Scholar
  56. 56.
    Zhu M, Li J, Fink AL (2003) The association of α-synuclein with membranes affects bilayer structure, stability and fibril formation. J Biol Chem 278:40186–40197.PubMedGoogle Scholar
  57. 57.
    Martinez Z, Zhu M, Han S Fink AL (2007) GM1 specifically interacts with alpha-synuclein and inhibits fibrillation. Biochemistry 46:1868–1877.PubMedGoogle Scholar
  58. 58.
    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.PubMedGoogle Scholar
  59. 59.
    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.PubMedGoogle Scholar
  60. 60.
    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.PubMedGoogle Scholar
  61. 61.
    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.PubMedGoogle Scholar
  62. 62.
    Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L (2008) Wild type α-synuclein is degraded by chaperone mediated autophagy and macroautophagy in neuronal cells. J Biol Chem 283:23542–23556.PubMedGoogle Scholar
  63. 63.
    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.PubMedGoogle Scholar
  64. 64.
    Tanaka Y, Engelender S, Igarashi S, Rao RK, Wanner T, Tanzi RE, Sawa A, Dawson VL, Dawson TM, Ross CA (2001) Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum Mol Genet 10:919–926.PubMedGoogle Scholar
  65. 65.
    Petrucelli L, O’Farrell C, Lockhart PJ, Baptista M, Kehoe K, Vink L, Choi P, Wolozin B, Farrer M, Hardy J et al (2002) Parkin protects against the toxicity associated with mutant α-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36:1007–1019.PubMedGoogle Scholar
  66. 66.
    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.PubMedGoogle Scholar
  67. 67.
    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.PubMedGoogle Scholar
  68. 68.
    Zhang NY, Tang Z, Liu CW (2008) Alpha-synuclein protofibrils inhibit 26S proteasome-mediated protein degradation. Understanding the cytotoxicity of protein protofibrils in neurodegenerative diseases pathogenesis. J Biol Chem. 283:20288–20298.PubMedGoogle Scholar
  69. 69.
    Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985–989.PubMedGoogle Scholar
  70. 70.
    Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K Iwatsubo T (2002) Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164.PubMedGoogle Scholar
  71. 71.
    Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ, Barbour R, Huang J, Kling K, Lee M et al (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281:29739–29752.PubMedGoogle Scholar
  72. 72.
    Mirzaei H, Schieler JL, Rochet JC, Regnier F (2006) Identification of rotenone-induced modifications in alpha-synuclein using affinity pull-down and tandem mass spectrometry. Anal Chem 78:2422–2431.PubMedGoogle Scholar
  73. 73.
    Smith WW, Margolis RL, Li X, Troncoso JC, Lee MK, Dawson VL, Dawson TM, Iwatsubo T, Ross CA (2005) Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J Neurosci 25:5544–5552.PubMedGoogle Scholar
  74. 74.
    Przedborski S, Chen Q, Vila M, Giasson BI, Djaldatti R, Vukosavic S, Souza JM, Jackson-Lewis V, Lee VM, Ischiropoulos H (2001) Oxidative post-translational modifications of alpha-synuclein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. J Neurochem 76:637–640.PubMedGoogle Scholar
  75. 75.
    Neumann M, Kahle PJ, Giasson BI, Ozmen L, Borroni E, Spooren W, Muller V, Odoy S, Fujiwara H, Hasegawa M et al (2002) Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies. J Clin Invest 110:1429–1439.PubMedGoogle Scholar
  76. 76.
    Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, Masliah E (1999) Oxidative stress induces amyloid-like aggregate formation of NACP/alpha-synuclein in vitro. Neuroreport 10:717–721.PubMedGoogle Scholar
  77. 77.
    Paik SR, Shin HJ, Lee JH (2000) Metal-catalyzed oxidation of alpha-synuclein in the presence of Copper(II) and hydrogen peroxide. Arch Biochem Biophys 378:269–277.PubMedGoogle Scholar
  78. 78.
    Souza JM, Giasson BI, Chen Q, Lee VM, Ischiropoulos H (2000) Dityrosine cross-linking promotes formation of stable alpha -synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J Biol Chem 275:18344–18349.PubMedGoogle Scholar
  79. 79.
    Krishnan S, Chi EY, Wood SJ, Kendrick BS, Li C, Garzon-Rodriguez W, Wypych J, Randolph TW, Narhi LO, Biere AL et al (2003) Oxidative dimer formation is the critical rate-limiting step for Parkinson’s disease alpha-synuclein fibrillogenesis. Biochemistry 42:829–837.PubMedGoogle Scholar
  80. 80.
    Zhou W, Freed CR (2004) Tyrosine-to-cysteine modification of human alpha-synuclein enhances protein aggregation and cellular toxicity. J Biol Chem 279:10128–10135.PubMedGoogle Scholar
  81. 81.
    Norris EH, Giasson BI, Ischiropoulos H, Lee VM (2003) Effects of oxidative and nitrative challenges on α-synuclein fibrillogenesis involve distinct mechanisms of protein modifications. J Biol Chem 278:27230–27240.PubMedGoogle Scholar
  82. 82.
    Yamin G, Uversky VN, Fink AL (2003) Nitration inhibits fibrillation of human alpha-synuclein in vitro by formation of soluble oligomers. FEBS Lett 542:147–152.PubMedGoogle Scholar
  83. 83.
    Cole NB, Murphy DD, Lebowitz J, Di Noto L, Levine RL, Nussbaum RL (2005) Metal-catalyzed oxidation of alpha-synuclein: helping to define the relationship between oligomers, protofibrils, and filaments. J Biol Chem 280:9678–9690.PubMedGoogle Scholar
  84. 84.
    Conway KA, Rochet JC, Bieganski RM, Lansbury PT Jr (2001) Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science 294:1346–1349.PubMedGoogle Scholar
  85. 85.
    Cappai R, Leck SL, Tew DJ, Williamson NA, Smith DP, Galatis D, Sharples RA, Curtain CC, Ali FE, Cherny RA et al (2005) Dopamine promotes alpha-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway. Faseb J 19:1377–1379.PubMedGoogle Scholar
  86. 86.
    Li HT, Lin DH, Luo XY, Zhang F, Ji LN, Du HN, Song GQ, Hu J, Zhou JW, Hu HY (2005) Inhibition of alpha-synuclein fibrillization by dopamine analogs via reaction with the amino groups of alpha-synuclein. Implication for dopaminergic neurodegeneration. FEBS J 272:3661–3672.PubMedGoogle Scholar
  87. 87.
    Bisaglia M, Mammi S, Bubacco L (2007) Kinetic and structural analysis of the early oxidation products of dopamine. Analysis of the interactions with alpha-synuclein. J Biol Chem 282:15597–15605.PubMedGoogle Scholar
  88. 88.
    Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A et al (2008) Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Invest 118:777–788.PubMedGoogle Scholar
  89. 89.
    Li J, Zhu M, Manning-Bog AB, Di Monte DA, Fink AL (2004) Dopamine and L-dopa disaggregate amyloid fibrils: implications for Parkinson’s and Alzheimer’s disease. Faseb J 18:962–964.PubMedGoogle Scholar
  90. 90.
    Norris EH, Giasson BI, Hodara R, Xu S, Trojanowski JQ, Ischiropoulos H, Lee VM (2005) Reversible inhibition of alpha-synuclein fibrillization by dopaminochrome-mediated conformational alterations. J Biol Chem 280:21212–21219.PubMedGoogle Scholar
  91. 91.
    Follmer C, Romao L, Einsiedler CM, Porto TC, Lara FA, Moncores M, Weissmuller G, Lashuel HA, Lansbury P, Neto VM et al (2007) Dopamine affects the stability, hydration, and packing of protofibrils and fibrils of the wild type and variants of alpha-synuclein. Biochemistry 46:472–482.PubMedGoogle Scholar
  92. 92.
    Chae SW, Kang BY, Hwang O, Choi HJ (2008) Cyclooxygenase-2 is involved in oxidative damage and alpha-synuclein accumulation in dopaminergic cells. Neurosci Lett 436:205–209.PubMedGoogle Scholar
  93. 93.
    Hokenson MJ, Uversky VN, Goers J, Yamin G, Munishkina LA, Fink AL (2004) Role of individual methionines in the fibrillation of methionine-oxidized alpha-synuclein. Biochemistry 43:4621–4633.PubMedGoogle Scholar
  94. 94.
    Yamin G, Glaser CB, Uversky VN, Fink AL (2003) Certain metals trigger fibrillation of methionine-oxidized α-synuclein. J Biol Chem 278:27630–27635.PubMedGoogle Scholar
  95. 95.
    Uversky VN, Yamin G, Souillac PO, Goers J, Glaser CB Fink AL (2002) Methionine oxidation inhibits fibrillation of human α-synuclein in vitro. FEBS Lett 517:239–244.PubMedGoogle Scholar
  96. 96.
    Glaser CB, Yamin G, Uversky VN, Fink AL (2005) Methionine oxidation, alpha-synuclein and Parkinson’s disease. Biochim Biophys Acta 1703:157–169.PubMedGoogle Scholar
  97. 97.
    Qin Z, Hu D, Han S, Reaney SH, Di Monte DA, Fink AL (2007) Effect of 4-hydroxy-2-nonenal modification on alpha-synuclein aggregation. J Biol Chem 282:5862–5870.PubMedGoogle Scholar
  98. 98.
    Shamoto-Nagai M, Maruyama W, Hashizume Y, Yoshida M, Osawa T, Riederer P, Naoi M (2007) In parkinsonian substantia nigra, alpha-synuclein is modified by acrolein, a lipid-peroxidation product, and accumulates in the dopamine neurons with inhibition of proteasome activity. J Neural Transm 114:1559–1567.PubMedGoogle Scholar
  99. 99.
    Bosco DA, Fowler DM, Zhang Q, Nieva J, Powers ET, Wentworth P Jr, Lerner RA, Kelly JW (2006) Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization. Nat Chem Biol 2:249–253.PubMedGoogle Scholar
  100. 100.
    Paleologou KE, Schmid AW, Rospigliosi CC, Kim HY, Lamberto GR, Fredenburg RA, Lansbury PT Jr, Fernandez CO, Eliezer D, Zweckstetter M et al (2008) Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of alpha-synuclein. J Biol Chem 283:16895–16905.PubMedGoogle Scholar
  101. 101.
    Hoyer W, Antony T, Cherny D, Heim G, Jovin TM, Subramaniam V (2002) Dependence of alpha-synuclein aggregate morphology on solution conditions. J Mol Biol 322:383–393.PubMedGoogle Scholar
  102. 102.
    Pronin AN, Morris AJ, Surguchov A, Benovic JL (2000) Synucleins are a novel class of substrates for G protein-coupled receptor kinases. J Biol Chem 275:26515–26522.PubMedGoogle Scholar
  103. 103.
    Chen L Feany MB (2005) Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 8:657–663.PubMedGoogle Scholar
  104. 104.
    Gorbatyuk OS, Li S, Sullivan LF, Chen W, Kondrikova G, Manfredsson FP, Mandel RJ, Muzyczka N (2008) The phosphorylation state of Ser-129 in human alpha-synuclein determines neurodegeneration in a rat model of Parkinson disease. Proc Natl Acad Sci USA 105:763–768.PubMedGoogle Scholar
  105. 105.
    Moskovitz J, Berlett BS, Poston JM, Stadtman ER (1997) The yeast peptide-methionine sulfoxide reductase functions as an antioxidant in vivo. Proc Natl Acad Sci USA 94:9585–9589.PubMedGoogle Scholar
  106. 106.
    Moskovitz J, Flescher E, Berlett BS, Azare J, Poston JM, Stadtman ER (1998) Overexpression of peptide-methionine sulfoxide reductase in Saccharomyces cerevisiae and human T cells provides them with high resistance to oxidative stress. Proc Natl Acad Sci USA 95:14071–14075.PubMedGoogle Scholar
  107. 107.
    Yermolaieva O, Xu R, Schinstock C, Brot N, Weissbach H, Heinemann SH, Hoshi T (2004) Methionine sulfoxide reductase A protects neuronal cells against brief hypoxia/reoxygenation. Proc Natl Acad Sci USA 101:1159–1164.PubMedGoogle Scholar
  108. 108.
    Marchetti MA, Lee W, Cowell TL, Wells TM, Weissbach H, Kantorow M (2006) Silencing of the methionine sulfoxide reductase A gene results in loss of mitochondrial membrane potential and increased ROS production in human lens cells. Exp Eye Res 83:1281–1286.PubMedGoogle Scholar
  109. 109.
    Moskovitz J, Bar-Noy S, Williams WM, Requena J, Berlett BS, Stadtman ER (2001) Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals. Proc Natl Acad Sci USA 98:12920–12925.PubMedGoogle Scholar
  110. 110.
    Stadtman ER, Moskovitz J, Berlett BS, Levine RL (2002) Cyclic oxidation and reduction of protein methionine residues is an important antioxidant mechanism. Mol Cell Biochem 234–235:3–9.Google Scholar
  111. 111.
    Petropoulos I, Mary J, Perichon M, Friguet B (2001) Rat peptide methionine sulphoxide reductase: cloning of the cDNA, and down-regulation of gene expression and enzyme activity during aging. Biochem J 355:819–825.PubMedGoogle Scholar
  112. 112.
    Ruan H, Tang XD, Chen ML, Joiner ML, Sun G, Brot N, Weissbach H, Heinemann SH, Iverson L, Wu CF et al (2002) High-quality life extension by the enzyme peptide methionine sulfoxide reductase. Proc Natl Acad Sci USA 99:2748–2753.PubMedGoogle Scholar
  113. 113.
    Levine RL, Moskovitz J, Stadtman ER (2000) Oxidation of methionine in proteins: roles in antioxidant defense and cellular regulation. IUBMB Life 50:301–307.PubMedGoogle Scholar
  114. 114.
    Moskovitz J, Jenkins NA, Gilbert DJ, Copeland NG, Jursky F, Weissbach H, Brot N (1996) Chromosomal localization of the mammalian peptide-methionine sulfoxide reductase gene and its differential expression in various tissues. Proc Natl Acad Sci USA 93:3205–3208.PubMedGoogle Scholar
  115. 115.
    Liu F, Hindupur J, Nguyen JL, Ruf KJ, Zhu J, Schieler JL, Bonham CC, Wood KV, Davisson VJ, Rochet JC (2008) Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson’s disease-related insults. Free Radic Biol Med 45:242–255.PubMedGoogle Scholar
  116. 116.
    Liu F, Nguyen JL, Hulleman JD, Li L, Rochet JC (2008) Mechanisms of DJ-1 neuroprotection in a cellular model of Parkinson’s disease. J Neurochem 105:2435–2453.Google Scholar
  117. 117.
    Jenner P, Olanow CW (1998) Understanding cell death in Parkinson’s disease. Ann Neurol 44:S72–84.PubMedGoogle Scholar
  118. 118.
    Bharath S, Hsu M, Kaur D, Rajagopalan S, Andersen JK (2002) Glutathione, iron and Parkinson’s disease. Biochem Pharmacol 64:1037–1048.PubMedGoogle Scholar
  119. 119.
    Maher P (2005) The effects of stress and aging on glutathione metabolism. Ageing Res Rev 4:288–314.PubMedGoogle Scholar
  120. 120.
    Wassef R, Haenold R, Hansel A, Brot N, Heinemann SH, Hoshi T (2007) Methionine sulfoxide reductase A and a dietary supplement S-methyl-L-cysteine prevent Parkinson’s-like symptoms. J Neurosci 27:12808–12816.PubMedGoogle Scholar
  121. 121.
    Zhou W, Freed CR (2005) DJ-1 up-regulates glutathione synthesis during oxidative stress and inhibits A53T alpha-synuclein toxicity. J Biol Chem 280:43150–43158.PubMedGoogle Scholar
  122. 122.
    Botella JA, Bayersdorfer F Schneuwly S (2008) Superoxide dismutase overexpression protects dopaminergic neurons in a Drosophila model of Parkinson’s disease. Neurobiol Dis 30:65–73.PubMedGoogle Scholar
  123. 123.
    Trinh K, Moore K, Wes PD, Muchowski PJ, Dey J, Andrews L, Pallanck LJ (2008) Induction of the phase II detoxification pathway suppresses neuron loss in Drosophila models of Parkinson’s disease. J Neurosci 28:465–472.PubMedGoogle Scholar
  124. 124.
    Kim HY, Gladyshev VN (2005) Role of structural and functional elements of mouse methionine-S-sulfoxide reductase in its subcellular distribution. Biochemistry 44:8059–8067.PubMedGoogle Scholar
  125. 125.
    Cole NB, Dieuliis D, Leo P, Mitchell DC Nussbaum RL (2008) Mitochondrial translocation of alpha-synuclein is promoted by intracellular acidification. Exp Cell Res 314:2076–2089.PubMedGoogle Scholar
  126. 126.
    Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anandatheerthavarada HK (2008) Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem 283:9089–9100.PubMedGoogle Scholar
  127. 127.
    Li J, Zhu M, Rajamani S, Uversky VN, Fink AL (2004) Rifampicin inhibits alpha-synuclein fibrillation and disaggregates fibrils. Chem Biol 11:1513–1521.PubMedGoogle Scholar
  128. 128.
    Zhu M, Rajamani S, Kaylor J, Han S, Zhou F Fink AL (2004) The flavonoid baicalein inhibits fibrillation of alpha-synuclein and disaggregates existing fibrils. J Biol Chem 279:26846–26857.PubMedGoogle Scholar
  129. 129.
    Masuda M, Suzuki N, Taniguchi S, Oikawa T, Nonaka T, Iwatsubo T, Hisanaga S, Goedert M, Hasegawa M (2006) Small molecule inhibitors of alpha-synuclein filament assembly. Biochemistry 45:6085–6094.PubMedGoogle Scholar
  130. 130.
    Ono K, Yamada M (2006) Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. J Neurochem 97:105–115.PubMedGoogle Scholar
  131. 131.
    Ehrnhoefer DE, Bieschke J, Boeddrich A, Herbst M, Masino L, Lurz R, Engemann S, Pastore A Wanker EE (2008) EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat Struct Mol Biol 15:558–566.PubMedGoogle Scholar
  132. 132.
    Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE (2008) Curcumin inhibits aggregation of alpha-synuclein. Acta Neuropathol 115:479–489.PubMedGoogle Scholar
  133. 133.
    Kostka M, Hogen T, Danzer KM, Levin J, Habeck M, Wirth A, Wagner R, Glabe CG, Finger S, Heinzelmann U et al (2008) Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers. J Biol Chem 283:10992–11003.PubMedGoogle Scholar
  134. 134.
    Muchowski PJ, Wacker JL (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6:11–22.PubMedGoogle Scholar
  135. 135.
    Rochet JC (2007) Novel therapeutic strategies for the treatment of protein-misfolding diseases. Expert Rev Mol Med 9:1–34.PubMedGoogle Scholar
  136. 136.
    Dedmon MM, Christodoulou J, Wilson MR, Dobson CM (2005) Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species. J Biol Chem 280:14733–14740.PubMedGoogle Scholar
  137. 137.
    Huang C, Cheng H, Hao S, Zhou H, Zhang X, Gao J, Sun QH, Hu H, Wang CC (2006) Heat shock protein 70 inhibits alpha-synuclein fibril formation via interactions with diverse intermediates. J Mol Biol 364:323–336.PubMedGoogle Scholar
  138. 138.
    Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295:865–868.PubMedGoogle Scholar
  139. 139.
    Auluck PK, Meulener MC, Bonini NM (2005) Mechanisms of suppression of alpha-synuclein neurotoxicity by geldanamycin in Drosophila. J Biol Chem 280:2873–2878.PubMedGoogle Scholar
  140. 140.
    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 279:39155–39164.PubMedGoogle Scholar
  141. 141.
    Klucken J, Shin Y, Masliah E, Hyman BT, McLean PJ (2004) Hsp70 Reduces alpha-synuclein Aggregation and Toxicity. J Biol Chem 279:25497–25502.PubMedGoogle Scholar
  142. 142.
    McLean PJ, Klucken J, Shin Y, Hyman BT (2004) Geldanamycin induces Hsp70 and prevents alpha-synuclein aggregation and toxicity in vitro. Biochem Biophys Res Commun 321:665–669.PubMedGoogle Scholar
  143. 143.
    Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen R, Koker M, Carvalho F, Hyman BT, McLean PJ (2008) Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS ONE 3:e1867.PubMedGoogle Scholar
  144. 144.
    Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269.PubMedGoogle Scholar
  145. 145.
    Rekas A, Adda CG, Andrew Aquilina J, Barnham KJ, Sunde M, Galatis D, Williamson NA, Masters CL, Anders RF, Robinson CV et al (2004) Interaction of the molecular chaperone alphaB-crystallin with alpha-synuclein: effects on amyloid fibril formation and chaperone activity. J Mol Biol 340:1167–1183.PubMedGoogle Scholar
  146. 146.
    Rekas A, Jankova L, Thorn DC, Cappai R, Carver JA (2007) Monitoring the prevention of amyloid fibril formation by alpha-crystallin. Temperature dependence and the nature of the aggregating species. FEBS J 274:6290–6304.PubMedGoogle Scholar
  147. 147.
    Ecroyd H, Carver JA (2008) The effect of small molecules in modulating the chaperone activity of alphaB-crystallin against ordered and disordered protein aggregation. FEBS J 275:935–947.PubMedGoogle Scholar
  148. 148.
    Ahmad MF, Raman B, Ramakrishna T, Rao Ch M (2008) Effect of phosphorylation on alpha B-crystallin: differences in stability, subunit exchange and chaperone activity of homo and mixed oligomers of alpha B-crystallin and its phosphorylation-mimicking mutant. J Mol Biol 375:1040–1051.PubMedGoogle Scholar
  149. 149.
    Ghosh JG, Houck SA, Clark JI (2008) Interactive sequences in the molecular chaperone, human alphaB crystallin modulate the fibrillation of amyloidogenic proteins. Int J Biochem Cell Biol 40:954–967.PubMedGoogle Scholar
  150. 150.
    Zourlidou A, Payne Smith MD, Latchman DS (2004) HSP27 but not HSP70 has a potent protective effect against alpha-synuclein-induced cell death in mammalian neuronal cells. J Neurochem 88:1439–1448.PubMedGoogle Scholar
  151. 151.
    Outeiro TF, Klucken J, Strathearn KE, Liu F, Nguyen P, Rochet JC, Hyman BT, McLean PJ (2006) Small heat shock proteins protect against alpha-synuclein-induced toxicity and aggregation. Biochem Biophys Res Commun 351:631–638.PubMedGoogle Scholar
  152. 152.
    Pountney DL, Treweek TM, Chataway T, Huang Y, Chegini F, Blumbergs PC, Raftery MJ, Gai WP (2005) Alpha B-crystallin is a major component of glial cytoplasmic inclusions in multiple system atrophy. Neurotox Res 7:77–85.PubMedGoogle Scholar
  153. 153.
    Uryu K, Richter-Landsberg C, Welch W, Sun E, Goldbaum O, Norris EH, Pham CT, Yazawa I, Hilburger K, Micsenyi M et al (2006) Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies. Am J Pathol 168:947–961.PubMedGoogle Scholar
  154. 154.
    Wang L, Xie C, Greggio E, Parisiadou L, Shim H, Sun L, Chandran J, Lin X, Lai C, Yang WJ et al (2008) The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2. J Neurosci 28:3384–3391.PubMedGoogle Scholar
  155. 155.
    Cao S, Gelwix CC, Caldwell KA, Caldwell GA (2005) Torsin-mediated protection from cellular stress in the dopaminergic neurons of Caenorhabditis elegans. J Neurosci 25:3801–3812.PubMedGoogle Scholar
  156. 156.
    Sharma N, Hewett J, Ozelius LJ, Ramesh V, McLean PJ, Breakefield XO, Hyman BT (2001) A close association of torsinA and alpha-synuclein in Lewy bodies: a fluorescence resonance energy transfer study. Am J Pathol 159:339–344.PubMedGoogle Scholar
  157. 157.
    McLean PJ, Kawamata H, Shariff S, Hewett J, Sharma N, Ueda K, Breakefield XO, Hyman BT (2002) TorsinA and heat shock proteins act as molecular chaperones: suppression of alpha-synuclein aggregation. J Neurochem 83:846–854.PubMedGoogle Scholar
  158. 158.
    Abou-Sleiman PM, Healy DG, Quinn N, Lees AJ, Wood NW (2003) The role of pathogenic DJ-1 mutations in Parkinson’s disease. Ann Neurol 54:283–286.PubMedGoogle Scholar
  159. 159.
    Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M et al (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259.PubMedGoogle Scholar
  160. 160.
    Hering R, Strauss KM, Tao X, Bauer A, Woitalla D, Mietz EM, Petrovic S, Bauer P, Schaible W, Muller T et al (2004) Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7). Hum Mutat 24:321–329.PubMedGoogle Scholar
  161. 161.
    Annesi G, Savettieri G, Pugliese P, D’Amelio M, Tarantino P, Ragonese P, La Bella V, Piccoli T, Civitelli D, Annesi F et al (2005) DJ-1 mutations and parkinsonism-dementia-amyotrophic lateral sclerosis complex. Ann Neurol 58:803–807.PubMedGoogle Scholar
  162. 162.
    Lev N, Roncevic D, Ickowicz D, Melamed E, Offen D (2006) Role of DJ-1 in Parkinson’s disease. J Mol Neurosci 29:215–225.PubMedGoogle Scholar
  163. 163.
    Tang B, Xiong H, Sun P, Zhang Y, Wang D, Hu Z, Zhu Z, Ma H, Pan Q, Xia JH et al (2006) Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson’s disease. Hum Mol Genet 15:1816–1825.PubMedGoogle Scholar
  164. 164.
    Honbou K, Suzuki NN, Horiuchi M, Niki T, Taira T, Ariga H, Inagaki F (2003) The crystal structure of DJ-1, a protein related to male fertility and Parkinson’s disease. J Biol Chem 278:31380–31384.PubMedGoogle Scholar
  165. 165.
    Huai Q, Sun Y, Wang H, Chin LS, Li L, Robinson H, Ke H (2003) Crystal structure of DJ-1/RS and implication on familial Parkinson’s disease. FEBS Lett 549:171–175.PubMedGoogle Scholar
  166. 166.
    Lee SJ, Kim SJ, Kim IK, Ko J, Jeong CS, Kim GH, Park C, Kang SO, Suh PG, Lee HS et al (2003) Crystal structures of human DJ-1 and Escherichia coli Hsp31, which share an evolutionarily conserved domain. J Biol Chem 278:44552–44559.PubMedGoogle Scholar
  167. 167.
    Tao X, Tong L (2003) Crystal structure of human DJ-1, a protein associated with early onset Parkinson’s disease. J Biol Chem 278:31372–31379.PubMedGoogle Scholar
  168. 168.
    Wilson MA, Collins JL, Hod Y, Ringe D, Petsko GA (2003) The 1.1-A resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson’s disease. Proc Natl Acad Sci USA 100:9256–9261.PubMedGoogle Scholar
  169. 169.
    Canet-Aviles RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, Baptista MJ, Ringe D, Petsko GA, Cookson MR (2004) The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci USA 101:9103–9108.PubMedGoogle Scholar
  170. 170.
    Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H (2004) DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep 5:213–218.PubMedGoogle Scholar
  171. 171.
    Yokota T, Sugawara K, Ito K, Takahashi R, Ariga H, Mizusawa H (2003) Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. Biochem Biophys Res Commun 312:1342–1348.PubMedGoogle Scholar
  172. 172.
    Martinat C, Shendelman S, Jonason A, Leete T, Beal MF, Yang L, Floss T, Abeliovich A (2004) Sensitivity to oxidative stress in DJ-1-deficient dopamine neurons: an ES- derived cell model of primary parkinsonism. PLoS Biol 2:e327.PubMedGoogle Scholar
  173. 173.
    Kim RH, Smith PD, Aleyasin H, Hayley S, Mount MP, Pownall S, Wakeham A, You-Ten AJ, Kalia SK, Horne P et al (2005) Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci USA 102:5215–5220.PubMedGoogle Scholar
  174. 174.
    Menzies FM, Yenisetti SC, Min KT (2005) Roles of Drosophila DJ-1 in survival of dopaminergic neurons and oxidative stress. Curr Biol 15:1578–1582.PubMedGoogle Scholar
  175. 175.
    Xu J, Zhong N, Wang H, Elias JE, Kim CY, Woldman I, Pifl C, Gygi SP, Geula C Yankner BA (2005) The Parkinson’s disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis. Hum Mol Genet 14:1231–1241.PubMedGoogle Scholar
  176. 176.
    Yang Y, Gehrke S, Haque ME, Imai Y, Kosek J, Yang L, Beal MF, Nishimura I, Wakamatsu K, Ito S et al (2005) Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Proc Natl Acad Sci USA 102:13670–13675.PubMedGoogle Scholar
  177. 177.
    Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco TM, Thomas B, Ko HS, Sasaki M, Ischiropoulos H, Przedborski S et al (2007) DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc Natl Acad Sci USA 104:14807–14812.PubMedGoogle Scholar
  178. 178.
    Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP (2006) DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci USA 103:15091–15096.PubMedGoogle Scholar
  179. 179.
    Shendelman S, Jonason A, Martinat C, Leete T Abeliovich A (2004) DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol 2:e362.PubMedGoogle Scholar
  180. 180.
    Zhou W, Zhu M, Wilson MA, Petsko GA, Fink AL (2006) The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein. J Mol Biol 356:1036–1048.PubMedGoogle Scholar
  181. 181.
    Batelli S, Albani D, Rametta R, Polito L, Prato F, Pesaresi M, Negro A, Forloni G (2008) DJ-1 modulates alpha-synuclein aggregation state in a cellular model of oxidative stress: relevance for Parkinson’s disease and involvement of HSP70. PLoS ONE 3:e1884.PubMedGoogle Scholar
  182. 182.
    Junn E, Taniguchi H, Jeong BS, Zhao X, Ichijo H, Mouradian MM (2005) Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Proc Natl Acad Sci USA 102:9691–9696.PubMedGoogle Scholar
  183. 183.
    Gorner K, Holtorf E, Waak J, Pham TT, Vogt-Weisenhorn DM, Wurst W, Haass C, Kahle PJ (2007) Structural determinants of the C-terminal helix-kink-helix motif essential for protein stability and survival promoting activity of DJ-1. J Biol Chem 282:13680–13691.PubMedGoogle Scholar
  184. 184.
    Fan J, Ren H, Jia N, Fei E, Zhou T, Jiang P, Wu M, Wang G (2008) DJ-1 decreases Bax expression through repressing p53 transcriptional activity. J Biol Chem 283:4022–4030.PubMedGoogle Scholar
  185. 185.
    Miyazaki S, Yanagida T, Nunome K, Ishikawa S, Inden M, Kitamura Y, Nakagawa S, Taira T, Hirota K, Niwa M et al (2008) DJ-1-binding compounds prevent oxidative stress-induced cell death and movement defect in Parkinson’s disease model rats. J Neurochem 105:2418–2434.Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Jean-Christophe Rochet
    • 1
  • Fang Liu
  1. 1.Department of Medicinal Chemistry and Molecular PharmacologyPurdue UniversityWest LafayetteUSA

Personalised recommendations