Reference : Identification and functional characterization of a novel R621C mutation in the synph...
Scientific journals : Article
Life sciences : Genetics & genetic processes
Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease.
Marx, Frank P. [> >]
Holzmann, Carsten [> >]
Strauss, Karsten M. [> >]
Li, Lei [> >]
Eberhardt, Olaf [> >]
Gerhardt, Ellen [> >]
Cookson, Mark R. [> >]
Hernandez, Dena [> >]
Farrer, Matt J. [> >]
Kachergus, Jennifer [> >]
Engelender, Simone [> >]
Ross, Christopher A. [> >]
Berger, Klaus [> >]
Schols, Ludger [> >]
Schulz, Jorg B. [> >]
Riess, Olaf [> >]
Krüger, Rejko mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Human molecular genetics
Yes (verified by ORBilu)
[en] Acetylcysteine/analogs & derivatives/pharmacology ; Adult ; Aged ; Amino Acid Sequence ; Carrier Proteins/drug effects/genetics/metabolism ; Case-Control Studies ; Cell Death/drug effects/genetics ; Cells, Cultured ; Cysteine Endopeptidases ; Cysteine Proteinase Inhibitors/pharmacology ; Female ; Green Fluorescent Proteins ; Humans ; Luminescent Proteins/genetics/metabolism ; Male ; Middle Aged ; Molecular Sequence Data ; Multienzyme Complexes/antagonists & inhibitors ; Mutation ; Nerve Tissue Proteins/drug effects/genetics/metabolism ; Neurons/drug effects/pathology/physiology ; Parkinson Disease/genetics ; Proteasome Endopeptidase Complex ; Recombinant Fusion Proteins/genetics/metabolism ; Staurosporine/pharmacology ; Synucleins ; Ubiquitin-Protein Ligases/genetics/metabolism ; alpha-Synuclein
[en] 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.
Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)

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