Abstract
Dysfunction of proteasomal protein degradation is involved in neurodegeneration in Parkinson’s disease (PD). Recently we identified the regulatory proteasomal subunit S6 ATPase as a novel interactor of synphilin-1, which is a substrate of the ubiquitin-ligase Parkin (PARK2) and an interacting protein of alpha-synuclein (PARK1). To further investigate a potential role in the pathogenesis of PD, we performed a detailed mutation analysis of the S6 ATPase gene in a large sample of 486 German sporadic and familial PD patients. Direct sequencing revealed two novel intronic variants. An insertion/deletion variant in intron 5 of the S6 ATPase gene was more frequent in patients compared to controls. Moreover, this variant was significantly more frequent in early-onset compared to late-onset PD patients. The identification of a genetic link between a regulatory proteasomal subunit and PD further underscores the relevance of disturbed protein degradation in PD.
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Belote JM, Fortier E (2002) Targeted expression of dominant negative proteasome mutants in Drosophila melanogaster. Genesis 34:80–82
Berg D, Niwar N, Maass S, Zimprich A, Moeller C, Wuellner U, Klein C, Tan E, Schoels L, Marsh L, Dawson T, Janetzky B, Dufke A, Bauer P, Krüger R, Gasser T, Riess O (2005) Mutations in the alpha-synuclein gene and Parkinson’s disease—implications from the screening of more than 1,900 patients. Mov Disord 20:1191–1194
Di Rocco A, Molinari SP, Kollmeier B, Yahr MD. (1996) Parkinson’s disease: progression and mortality in the l-DOPA era. Adv Neurol 69:3–11
Doss-Pepe EW, Stenroos ES, Johnson WG, Madura K (2003) Ataxin-3 interactions with rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis. Mol Cell Biol 23:6469–6483
Giasson BI, Uryu K, Trojanowski JQ, Lee VM. (1999) Mutant and wild type human alpha-synucleins assemble into elongated filaments with distinct morphologies in vitro. J Biol Chem 274:7619–7622
Gibb WRG, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 51:745–752
Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D, Artiguenave F, Davoine CS, Cruaud C, Durr A, Wincker P, Brottier P, Cattolico L, Barbe V, Burgunder JM, Prud’homme JF, Brice A, Fontaine B, Heilig B, Weissenbach J (1999) Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet 23:296–303
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
Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, Riess O (1998) Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat Genet 18:106–108
Krüger R, Eberhardt O, Riess O, Schulz JB (2002) Parkinson’s disease: one biochemical pathway to fit all genes? Trends Mol Med 8:236–240
Lam YA, Lawson TG, Velayutham M, Zweier JL, Pickart CM (2002) A proteasomal ATPase subunit recognizes the polyubiquitin degradation signal. Nature 416:763–767
Larsen CN, Finley D (1997) Protein translocation channels in the proteasome and other proteases. Cell 91: 431–434
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, Steinach PJ, Wilkinson KD, Polymeropoulos MH (1998) The ubiquitin pathway in Parkinson’s disease. Nature 395:451–452
Li Z, Arnaud L, Rockwell P, Figueiredo-Pereira ME (2004) A single amino acid substitution in a proteasome subunit triggers aggregation of ubiquitinated proteins in stressed neuronal cells. J Neurochem 90:19–28
Maraganore DM, Lesnick TG, Elbaz A, Chartier-Harlin MC, Gasser T, Sharma M, Krüger R, Riess O, Hattori N, Mellick GD, Quattrone A, Satoh JI, Toda T, Wang J, Ioannidis JPA, de Andrade M, Rocca WA, the UCH-L1 Global Genetics Consortium (2004) Collaborative reanalysis of the ubiquitin carboxy-terminal hydrolase L1 (UCHL-1) gene S18 variant and its association with Parkinson’ s disease (PD). Ann Neurol 55:512–521
Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Krüger R, Rocca WA, Schneider NK, Lesnick TG, Lincoln SJ, Hulihan MM, Aasly JO, Ashizawa T, Chartier-Harlin MC, Checkoway H, Ferrarese C, Hadjigeorgiou G, Hattori N, Kawakami H, Lambert JC, Lynch T, Mellick GD, Papapetropoulos S, Parsian A, Quattrone A, Riess O, Tan EK, Van Broeckhoven C, on behalf of the Genetic Epidemiology of Parkinson’s Disease (GEO-PD) Consortium. (2006) Collaborative analysis of alpha-synuclein gene protomer variability and Parkinson’s disease. JAMA 296:661–670
Marx FP, Holzmann C, Strauss KM, Li L, Eberhardt O, Gerhardt E, Cookson MR, Hernandez D, Farrer MJ, Kachergus J, Engelender S, Ross CA, Berger K, Schöls L, Schulz JB, Riess O, Krüger R (2003) Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease. Hum Mol Genet 12:1223–1231
Marx FP, Soehn AS, Berg D, Melle C, Schiesling C, Lang M, Kautzmann S, Strauss KM, Franck T, Engelender S, Pahnke J, Dawson S, von Eggeling F, Schulz JB, Riess O, Krüger R. (2007) The proteasomal subunit S6 ATPase is a novel synphilin-1 interacting protein – implications for Parkinson’s disease. FASEB J 21:1759–1767
Matilla A, Gorbea C, Einum DD, Townsend J, Michalik A, van Broeckhoven C, Jensen CC, Murphy K J, Ptacek LJ, Fu YH (2001) Association of ataxin-7 with the proteasome subunit S4 of the 19S regulatory complex. Hum Mol Genet 10:2821–2831
McNaught KSP, Jenner P (2001) Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci Lett 297:191–194
Oliveira SA, Scott WK, Martin ER, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Ondo WG, Allen FH Jr, Scott BL, Goetz CG, Small GW, Mastaglia F, Stajich JM, Zhang F, Booze MW, Winn MP, Middleton LT, Haines JL, Pericak-Vance MA, Vance JM (2003) Parkin mutations and susceptibility alleles in late-onset Parkinson’s disease. Ann Neurol 53:624–629
Ozelius LJ, Hewett JW, Page CE, Bressman SB, Kramer PL, Shalish C, de Leon D, Brin MF, Raymond D, Corey DP, Fahn S, Risch NJ, Buckler AJ, Gusella JF, Breakefield XO (1997) The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet 17:40–48
Pickart CM (2000) Ubiquitin in chains. Trends Biochem Sci 25:544–548
Raymond M, Rousset F. (1995) Genepop (version 1.2): population genetics software for exact tests and ecumenicism. J Hered 86:248–249
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
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840
Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, Gasser T, Wszolek Z, Müller T, Bornemann A, Wolburg H, Downward J, Riess O, Schulz JB, Krüger R (2005) Loss of function mutation in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet 14:2099–2111
Svejgaard A, Platz P, Ryder LP (1983) HLA and disease 1982—a survey. Immunol Rev 70:193–218
Voges D, Zwickl P, Baumeister W (1999) The 26S proteasome: a molecular machine designed for controlled proteolysis. Ann Rev Biochem 68:1015–1068
Wilkinson CR, Ferrell K, Penney M, Wallace M, Dubiel W, Gordon C (2000) Analysis of a gene encoding Rpn10 of the fission yeast proteasome reveals that the polyubiquitin-binding site of this subunit is essential when Rpn12/Mts3 activity is compromised. J Biol Chem 275:15182–15192
Yen HS, Espiritu C, Chang EC (2003) Rpn5 is a conserved proteasome subunit and required for proper proteasome localization and assembly. J Biol Chem 278:30669–30676
Acknowledgments
We thank the PD patients and healthy control individuals for their support. This study has been supported by a grant of the Fritz Thyssen Foundation and the German Research Council (DFG; KR2119/3-1) to R.K.
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Wahl, C., Kautzmann, S., Krebiehl, G. et al. A comprehensive genetic study of the proteasomal subunit S6 ATPase in German Parkinson’s disease patients. J Neural Transm 115, 1141–1148 (2008). https://doi.org/10.1007/s00702-008-0054-3
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DOI: https://doi.org/10.1007/s00702-008-0054-3