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Human Molecular Genetics, 2003, Vol. 12, No. 11 1223-1231
DOI: 10.1093/hmg/ddg134
© 2003 Oxford University Press

Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease

Frank P. Marx1, Carsten Holzmann2, Karsten M. Strauss1, Lei Li2,3, Olaf Eberhardt1, Ellen Gerhardt1, Mark R. Cookson4, Dena Hernandez4, Matt J. Farrer5, Jennifer Kachergus5, Simone Engelender6, Christopher A. Ross7, Klaus Berger8, Ludger Schöls9, Jörg B. Schulz1, Olaf Riess10 and Rejko Krüger1,*

1Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany, 2Department of Medical Genetics, University of Rostock, Rostock, Germany, 3Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical University, Wuhan, People's Republic of China, 4Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA, 5Neurogenetics Laboratory, Mayo Clinic, Jacksonville, USA, 6Department of Pharmacology, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel, 7Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 8Department of Epidemiology and Social Medicine, University of Münster, Germany, 9Neurology, University of Bochum, Bochum, Germany and 10Department of Medical Genetics, University of Tübingen, Tübingen, Germany

Received February 4, 2003; Accepted March 21, 2003

Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an {alpha}-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 compared with cells expressing wild-type (wt) synphilin-1, when subjected to proteasomal inhibition. C621 synphilin-1 transfected cells were more susceptible to staurosporine-induced cell death than cells expressing wt synphilin-1. Our findings argue in favour of a causative role of the R621C mutation in the synphilin-1 gene in PD and suggest that the formation of intracellular inclusions may be beneficial to cells and that a mutation in synphilin-1 that reduces this ability may sensitize neurons to cellular stress.

* To whom correspondence should be addressed at: Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Hoppe-Seyler-Str. 3, D-72076 Tübingen, Germany. Tel: +49 70712982141; Fax: +49 7071295260; Email: rejko.krueger{at}uni-tuebingen.de


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