title: Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease.
abstract: 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.
authors.affiliation: Department of Neurology, Laboratory of Neurodegeneration, University of Tübingen, Tübingen, Germany.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Marx
authors.forename: Carsten
authors.initials: C
authors.lastname: Holzmann
authors.forename: Karsten M
authors.initials: KM
authors.lastname: Strauss
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Olaf
authors.initials: O
authors.lastname: Eberhardt
authors.forename: Ellen
authors.initials: E
authors.lastname: Gerhardt
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Farrer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kachergus
authors.forename: Simone
authors.initials: S
authors.lastname: Engelender
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: Klaus
authors.initials: K
authors.lastname: Berger
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D010300:Parkinson Disease / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein
chemical_list: D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D008164:Luminescent Proteins; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C497604:SNCA protein, human; C118958:SNCAIP protein, human; D051843:Synucleins; D051844:alpha-Synuclein; C067713:lactacystin; D049452:Green Fluorescent Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D019311:Staurosporine; D000111:Acetylcysteine