Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease
Identifieur interne : 001754 ( Main/Exploration ); précédent : 001753; suivant : 001755Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease
Auteurs : Frank P. Marx ; Carsten Holzmann ; Karsten M. Strauss ; Lei Li ; Olaf Eberhardt ; Ellen Gerhardt ; Mark R. Cookson ; Dena Hernandez ; Matt J. Farrer ; Jennifer Kachergus ; Simone Engelender ; Christopher A. Ross ; Klaus Berger ; Ludger Scho Ls ; Jo Rg B. Schulz ; Olaf Riess [Allemagne] ; Rejko Kru GerSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2003-06-01.
Abstract
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.
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DOI: 10.1093/hmg/ddg134
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Genet.</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2003-06-01">2003-06-01</date><biblScope unit="volume">12</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="1223">1223</biblScope><biblScope unit="page" to="1231">1231</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">A26BAACBE6D61CBA3B0772B2E62FB05A9A9A8118</idno><idno type="DOI">10.1093/hmg/ddg134</idno><idno type="local">ddg134</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Allemagne</li></country></list><tree><noCountry><name sortKey="Berger, Klaus" sort="Berger, Klaus" uniqKey="Berger K" first="Klaus" last="Berger">Klaus Berger</name><name sortKey="Cookson, Mark R" sort="Cookson, Mark R" uniqKey="Cookson M" first="Mark R." last="Cookson">Mark R. 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Farrer</name><name sortKey="Gerhardt, Ellen" sort="Gerhardt, Ellen" uniqKey="Gerhardt E" first="Ellen" last="Gerhardt">Ellen Gerhardt</name><name sortKey="Hernandez, Dena" sort="Hernandez, Dena" uniqKey="Hernandez D" first="Dena" last="Hernandez">Dena Hernandez</name><name sortKey="Holzmann, Carsten" sort="Holzmann, Carsten" uniqKey="Holzmann C" first="Carsten" last="Holzmann">Carsten Holzmann</name><name sortKey="Kachergus, Jennifer" sort="Kachergus, Jennifer" uniqKey="Kachergus J" first="Jennifer" last="Kachergus">Jennifer Kachergus</name><name sortKey="Kru Ger, Rejko" sort="Kru Ger, Rejko" uniqKey="Kru Ger R" first="Rejko" last="Kru Ger">Rejko Kru Ger</name><name sortKey="Li, Lei" sort="Li, Lei" uniqKey="Li L" first="Lei" last="Li">Lei Li</name><name sortKey="Marx, Frank P" sort="Marx, Frank P" uniqKey="Marx F" first="Frank P." last="Marx">Frank P. Marx</name><name sortKey="Ross, Christopher A" sort="Ross, Christopher A" uniqKey="Ross C" first="Christopher A." last="Ross">Christopher A. Ross</name><name sortKey="Scho Ls, Ludger" sort="Scho Ls, Ludger" uniqKey="Scho Ls L" first="Ludger" last="Scho Ls">Ludger Scho Ls</name><name sortKey="Schulz, Jo Rg B" sort="Schulz, Jo Rg B" uniqKey="Schulz J" first="Jo Rg B." last="Schulz">Jo Rg B. Schulz</name><name sortKey="Strauss, Karsten M" sort="Strauss, Karsten M" uniqKey="Strauss K" first="Karsten M." last="Strauss">Karsten M. Strauss</name></noCountry><country name="Allemagne"><noRegion><name sortKey="Riess, Olaf" sort="Riess, Olaf" uniqKey="Riess O" first="Olaf" last="Riess">Olaf Riess</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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