A Caenorhabditis elegans Parkin mutant with altered solubility couples α-synuclein aggregation to proteotoxic stress
Identifieur interne : 001547 ( Main/Exploration ); précédent : 001546; suivant : 001548A Caenorhabditis elegans Parkin mutant with altered solubility couples α-synuclein aggregation to proteotoxic stress
Auteurs : Wolfdieter Springer ; Thorsten Hoppe ; Enrico Schmidt [Allemagne] ; Ralf Baumeister [Allemagne]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2005-11-15.
Abstract
Mutations in the human parkin gene encoding an E3 ubiquitin ligase have been associated with early-onset recessive forms of Parkinson's disease (PD). However, the molecular mechanisms by which mutations in the parkin gene cause PD are still under debate. Here, we identified and characterized the Caenorhabditis elegans parkin homolog, pdr-1. PDR-1 protein physically associates and cooperates with a conserved degradation machinery to mediate ubiquitin conjugation. Strikingly, in contrast to pdr-1 loss-of-function mutants, an in-frame deletion variant with altered solubility and intracellular localization properties is hypersensitive toward different proteotoxic stress conditions. Both endoplasmic reticulum-derived folding stress and cytosolic stress conferred by expression of mutant human α-synuclein resulted in severe developmental defects and lethality in pdr-1(lg103) mutant background. Furthermore, we show that the corresponding truncated protein PDR-1(Δaa24–247) aggregates in cell culture, but still interacts with its ubiquitylation co-enzymes. Thus, it might block the cellular degradation/detoxification machinery and therefore renders worms highly vulnerable to protein folding stress. In contrast to other complete gene knockouts or RNAi models of Parkin function, this C. elegans model recapitulates Parkin insolubility and aggregation similar to several autosomal recessive juvenile parkinsonism (AR-JP)-linked Parkin mutations. We suggest that such Parkin variants that either confer a neomorphic function or a partial loss-of-function may help to further elucidate the biological function of Parkin in vivo and the pathogenic mechanisms resulting in AR-JP. Due to high-throughput capacity of C. elegans, this model is particularly well suited to identify genetic and chemical modifiers of toxicity.
Url:
DOI: 10.1093/hmg/ddi371
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Caenorhabditis elegans Parkin mutant with altered solubility couples α-synuclein aggregation to proteotoxic stress</title><author><name sortKey="Springer, Wolfdieter" sort="Springer, Wolfdieter" uniqKey="Springer W" first="Wolfdieter" last="Springer">Wolfdieter Springer</name></author><author><name sortKey="Hoppe, Thorsten" sort="Hoppe, Thorsten" uniqKey="Hoppe T" first="Thorsten" last="Hoppe">Thorsten Hoppe</name></author><author><name sortKey="Schmidt, Enrico" sort="Schmidt, Enrico" uniqKey="Schmidt E" first="Enrico" last="Schmidt">Enrico Schmidt</name></author><author><name sortKey="Baumeister, Ralf" sort="Baumeister, Ralf" uniqKey="Baumeister R" first="Ralf" last="Baumeister">Ralf Baumeister</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:4982A222700AACA49CB20A4F265732AB43E85ABA</idno><date when="2005" year="2005">2005</date><idno type="doi">10.1093/hmg/ddi371</idno><idno type="url">https://api.istex.fr/document/4982A222700AACA49CB20A4F265732AB43E85ABA/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">003068</idno><idno type="wicri:Area/Main/Curation">002C73</idno><idno type="wicri:Area/Main/Exploration">001547</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">A Caenorhabditis elegans Parkin mutant with altered solubility couples α-synuclein aggregation to proteotoxic stress</title><author><name sortKey="Springer, Wolfdieter" sort="Springer, Wolfdieter" uniqKey="Springer W" first="Wolfdieter" last="Springer">Wolfdieter Springer</name><affiliation><wicri:noCountry code="subField">Germany and</wicri:noCountry></affiliation></author><author><name sortKey="Hoppe, Thorsten" sort="Hoppe, Thorsten" uniqKey="Hoppe T" first="Thorsten" last="Hoppe">Thorsten Hoppe</name><affiliation><wicri:noCountry code="subField">Germany and</wicri:noCountry></affiliation></author><author><name sortKey="Schmidt, Enrico" sort="Schmidt, Enrico" uniqKey="Schmidt E" first="Enrico" last="Schmidt">Enrico Schmidt</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Bio3/Bioinformatics and Molecular Genetics, University of Freiburg</wicri:regionArea><wicri:noRegion>University of Freiburg</wicri:noRegion><wicri:noRegion>University of Freiburg</wicri:noRegion></affiliation></author><author><name sortKey="Baumeister, Ralf" sort="Baumeister, Ralf" uniqKey="Baumeister R" first="Ralf" last="Baumeister">Ralf Baumeister</name><affiliation><wicri:noCountry code="subField">Germany and</wicri:noCountry></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Bio3/Bioinformatics and Molecular Genetics, University of Freiburg</wicri:regionArea><wicri:noRegion>University of Freiburg</wicri:noRegion><wicri:noRegion>University of Freiburg</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Allemagne</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><title level="j" type="abbrev">Hum. Mol. Genet.</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2005-11-15">2005-11-15</date><biblScope unit="volume">14</biblScope><biblScope unit="issue">22</biblScope><biblScope unit="page" from="3407">3407</biblScope><biblScope unit="page" to="3423">3423</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">4982A222700AACA49CB20A4F265732AB43E85ABA</idno><idno type="DOI">10.1093/hmg/ddi371</idno><idno type="href">ddi371</idno><idno type="local">ddi371</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">Mutations in the human parkin gene encoding an E3 ubiquitin ligase have been associated with early-onset recessive forms of Parkinson's disease (PD). However, the molecular mechanisms by which mutations in the parkin gene cause PD are still under debate. Here, we identified and characterized the Caenorhabditis elegans parkin homolog, pdr-1. PDR-1 protein physically associates and cooperates with a conserved degradation machinery to mediate ubiquitin conjugation. Strikingly, in contrast to pdr-1 loss-of-function mutants, an in-frame deletion variant with altered solubility and intracellular localization properties is hypersensitive toward different proteotoxic stress conditions. Both endoplasmic reticulum-derived folding stress and cytosolic stress conferred by expression of mutant human α-synuclein resulted in severe developmental defects and lethality in pdr-1(lg103) mutant background. Furthermore, we show that the corresponding truncated protein PDR-1(Δaa24–247) aggregates in cell culture, but still interacts with its ubiquitylation co-enzymes. Thus, it might block the cellular degradation/detoxification machinery and therefore renders worms highly vulnerable to protein folding stress. In contrast to other complete gene knockouts or RNAi models of Parkin function, this C. elegans model recapitulates Parkin insolubility and aggregation similar to several autosomal recessive juvenile parkinsonism (AR-JP)-linked Parkin mutations. We suggest that such Parkin variants that either confer a neomorphic function or a partial loss-of-function may help to further elucidate the biological function of Parkin in vivo and the pathogenic mechanisms resulting in AR-JP. Due to high-throughput capacity of C. elegans, this model is particularly well suited to identify genetic and chemical modifiers of toxicity.</div></front></TEI><affiliations><list><country><li>Allemagne</li></country></list><tree><noCountry><name sortKey="Hoppe, Thorsten" sort="Hoppe, Thorsten" uniqKey="Hoppe T" first="Thorsten" last="Hoppe">Thorsten Hoppe</name><name sortKey="Springer, Wolfdieter" sort="Springer, Wolfdieter" uniqKey="Springer W" first="Wolfdieter" last="Springer">Wolfdieter Springer</name></noCountry><country name="Allemagne"><noRegion><name sortKey="Schmidt, Enrico" sort="Schmidt, Enrico" uniqKey="Schmidt E" first="Enrico" last="Schmidt">Enrico Schmidt</name></noRegion><name sortKey="Baumeister, Ralf" sort="Baumeister, Ralf" uniqKey="Baumeister R" first="Ralf" last="Baumeister">Ralf Baumeister</name><name sortKey="Baumeister, Ralf" sort="Baumeister, Ralf" uniqKey="Baumeister R" first="Ralf" last="Baumeister">Ralf Baumeister</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001547 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 001547 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= ParkinsonV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= ISTEX:4982A222700AACA49CB20A4F265732AB43E85ABA
|texte= A Caenorhabditis elegans Parkin mutant with altered solubility couples α-synuclein aggregation to proteotoxic stress
}}
| This area was generated with Dilib version V0.6.23. |  |