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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 ; Schöls, Ludger ; Schulz, Jörg B. ; Riess, Olaf ; Krüger, Rejko

Human molecular genetics, 2003-06, Vol.12 (11), p.1223-1231 [Periódico revisado por pares]

Oxford: Oxford University Press

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Título:
Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease
Autor: 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 ; Schöls, Ludger ; Schulz, Jörg B. ; Riess, Olaf ; Krüger, Rejko
Assuntos: Acetylcysteine - analogs & derivatives ; Acetylcysteine - pharmacology ; Adult ; Aged ; alpha-Synuclein ; Amino Acid Sequence ; Biological and medical sciences ; Carrier Proteins - drug effects ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Case-Control Studies ; Cell Death - drug effects ; Cell Death - genetics ; Cells, Cultured ; Cysteine Endopeptidases ; Cysteine Proteinase Inhibitors - pharmacology ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Female ; Fundamental and applied biological sciences. Psychology ; Genes. Genome ; Green Fluorescent Proteins ; Humans ; Luminescent Proteins - genetics ; Luminescent Proteins - metabolism ; Male ; Medical sciences ; Middle Aged ; Molecular and cellular biology ; Molecular genetics ; Molecular Sequence Data ; Multienzyme Complexes - antagonists & inhibitors ; Mutation ; Nerve Tissue Proteins - drug effects ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Neurology ; Neurons - drug effects ; Neurons - pathology ; Neurons - physiology ; Parkinson Disease - genetics ; Proteasome Endopeptidase Complex ; Recombinant Fusion Proteins - genetics ; Recombinant Fusion Proteins - metabolism ; Staurosporine - pharmacology ; Synucleins ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism
É parte de: Human molecular genetics, 2003-06, Vol.12 (11), p.1223-1231
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Descrição: Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an α-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.
Editor: Oxford: Oxford University Press
Idioma: Inglês

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

Oxford: Oxford University Press

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