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Domain a’ of protein disulfide isomerase plays key role in inhibiting α-synuclein fibril formation

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Cell Stress and Chaperones Aims and scope

Abstract

α-Synuclein (αSyn) is the main component of Lewy bodies formed in midbrain dopaminergic neurons which is a pathological characteristic of Parkinson's disease. It has been recently showed to induce endoplasmic reticulum (ER) stress and impair ER functions. However, the mechanism of how ER responds to αSyn toxicity is poorly understood. In the present study, we found that protein disulfide isomerase (PDI), a stress protein abundant in ER, effectively inhibits αSyn fibril formation in vitro. In PDI molecule with a structure of abb’xa’c, domain a’ was found to be essential and sufficient for PDI to inhibit αSyn fibril formation. PDI was further found to be more avid for binding with intermediate species formed during αSyn fibril formation, and the binding was more intensive in the later lag phase. Our results provide new insight into the role of PDI in protecting ER from the deleterious effects of misfolded protein accumulation in many neurodegenerative diseases.

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References

  • Atkin JD, Farg MA, Turner BJ, Tomas D, Lysaght JA, Nunan J, Rembach A, Nagley P, Beart PM, Cheema SS et al (2006) Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. J Biol Chem 281:30152–30165

    Article  CAS  PubMed  Google Scholar 

  • Conn KJ, Gao W, McKee A, Lan MS, Ullman MD, Eisenhauer PB, Fine RE, Wells JM (2004) Identification of the protein disulfide isomerase family member PDIp in experimental Parkinson's disease and Lewy body pathology. Brain Res 1022:164–172

    Article  CAS  PubMed  Google Scholar 

  • Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PT Jr (2000) Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc Natl Acad Sci USA 97:571–576

    Article  CAS  PubMed  Google Scholar 

  • Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F et al (2006) Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 313:324–328

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Dixon C, Mathias N, Zweig RM, Davis DA, Gross DS (2005) Alpha-synuclein targets the plasma membrane via the secretory pathway and induces toxicity in yeast. Genetics 170:47–59

    Article  CAS  PubMed  Google Scholar 

  • Ellgaard L, Ruddock LW (2005) The human protein disulphide isomerase family: substrate interactions and functional properties. EMBO Rep 6:28–32

    Article  CAS  PubMed  Google Scholar 

  • Feany MB, Bender WW (2000) A Drosophila model of Parkinson's disease. Nature 404:394–398

    Article  CAS  PubMed  Google Scholar 

  • Gitler AD, Bevis BJ, Shorter J, Strathearn KE, Hamamichi S, Su LJ, Caldwell KA, Caldwell GA, Rochet JC, McCaffery JM et al (2008) The Parkinson's disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc Natl Acad Sci USA 105:145–150

    Article  CAS  PubMed  Google Scholar 

  • Gruber CW, Cemazar M, Heras B, Martin JL, Craik DJ (2006) Protein disulfide isomerase: the structure of oxidative folding. Trends Biochem Sci 31:455–464

    Article  CAS  PubMed  Google Scholar 

  • Huang C, Ren G, Zhou H, Wang CC (2005) A new method for purification of recombinant human alpha-synuclein in Escherichia coli. Protein Expr Purif 42:173–177

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Bjorklund A (2003) Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson's disease. Proc Natl Acad Sci USA 100:2884–2889

    Article  CAS  PubMed  Google Scholar 

  • Klappa P, Ruddock LW, Darby NJ, Freedman RB (1998) The b' domain provides the principal peptide-binding site of protein disulfide isomerase but all domains contribute to binding of misfolded proteins. EMBO J 17:927–935

    Article  CAS  PubMed  Google Scholar 

  • Kontopoulos E, Parvin JD, Feany MB (2006) Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet 15:3012–3023

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Lee HJ, Patel S, Lee SJ (2005) Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci 25:6016–6024

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Munoz E, Oliva R, Obach V, Marti MJ, Pastor P, Ballesta F, Tolosa E (1997) Identification of Spanish familial Parkinson's disease and screening for the Ala53Thr mutation of the alpha-synuclein gene in early onset patients. Neurosci Lett 235:57–60

    Article  CAS  PubMed  Google Scholar 

  • Papp E, Nardai G, Soti C, Csermely P (2003) Molecular chaperones, stress proteins and redox homeostasis. BioFactors 17:249–257

    Article  CAS  PubMed  Google Scholar 

  • Pirneskoski A, Klappa P, Lobell M, Williamson RA, Byrne L, Alanen HI, Salo KE, Kivirikko KI, Freedman RB, Ruddock LW (2004) Molecular characterization of the principal substrate binding site of the ubiquitous folding catalyst protein disulfide isomerase. J Biol Chem 279:10374–10381

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Savistchenko J, Krzewska J, Fay N, Melki R (2008) Molecular chaperones and the assembly of the prion Ure2p in vitro. J Biol Chem 283:15732–15739

    Article  CAS  PubMed  Google Scholar 

  • 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  CAS  PubMed  Google Scholar 

  • Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. Proc Natl Acad Sci USA 95:6469–6473

    Article  CAS  PubMed  Google Scholar 

  • Turano C, Coppari S, Altieri F, Ferraro A (2002) Proteins of the PDI family: unpredicted non-ER locations and functions. J Cell Physiol 193:154–163

    Article  CAS  PubMed  Google Scholar 

  • Uehara T, Nakamura T, Yao D, Shi ZQ, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA (2006) S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441:513–517

    Article  CAS  PubMed  Google Scholar 

  • Velazquez-Campoy A, Leavitt SA, Freire E (2004) Characterization of protein-protein interactions by isothermal titration calorimetry. Methods Mol Biol 261:35–54

    CAS  PubMed  Google Scholar 

  • Volles MJ, Lee SJ, Rochet JC, Shtilerman MD, Ding TT, Kessler JC, Lansbury PT Jr (2001) Vesicle permeabilization by protofibrillar alpha-synuclein: implications for the pathogenesis and treatment of Parkinson's disease. Biochemistry 40:7812–7819

    Article  CAS  PubMed  Google Scholar 

  • Wang HQ, Takahashi R (2007) Expanding insights on the involvement of endoplasmic reticulum stress in Parkinson's disease. Antioxid Redox Signal 9:553–561

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Li SJ, Sidhu A, Zhu L, Liang Y, Freedman RB, Wang CC (2009) Reconstitution of human Ero1-Lalpha/protein-disulfide isomerase oxidative folding pathway in vitro. Position-dependent differences in role between the a and a' domains of protein-disulfide isomerase. J Biol Chem 284:199–206

    Article  CAS  PubMed  Google Scholar 

  • Yao Y, Zhou Y, Wang C (1997) Both the isomerase and chaperone activities of protein disulfide isomerase are required for the reactivation of reduced and denatured acidic phospholipase A2. EMBO J 16:651–658

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Zhang C, Zhu Y, Cai Q, Chan P, Ueda K, Yu S, Yang H (2008) Semi-quantitative analysis of alpha-synuclein in subcellular pools of rat brain neurons: an immunogold electron microscopic study using a C-terminal specific monoclonal antibody. Brain Res 1244:40–52

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from Chinese Ministry of Science and Technology (2006CB806508 and 2006CB910903) and Chinese Academy of Sciences (KSCX2-YW-R-119). We sincerely thank Prof. Hongyu Hu for his generous gift of the plasmid of pET-3a containing human αSyn cDNA and Prof. Sarah Perrett of this Institute for her kind gift of Ure2p protein. Prof. Yigong Shi in Tsinghua University and Prof. Yi Liang in Wuhan University are appreciated for their kind help on ITC experiments.

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  1. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Han Cheng, Lei Wang & Chih-chen Wang

  2. Graduate School of the Chinese Academy of Sciences, Beijing, 100049, China

    Han Cheng

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  1. Han Cheng
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  2. Lei Wang
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Correspondence to Chih-chen Wang.

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Cheng, H., Wang, L. & Wang, Cc. Domain a’ of protein disulfide isomerase plays key role in inhibiting α-synuclein fibril formation. Cell Stress and Chaperones 15, 415–421 (2010). https://doi.org/10.1007/s12192-009-0157-2

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  • DOI: https://doi.org/10.1007/s12192-009-0157-2

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