Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila
Identifieur interne : 001B41 ( Main/Exploration ); précédent : 001B40; suivant : 001B42Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila
Auteurs : Tomoko Kanao ; Katerina Venderova ; David S. Park ; Terry Unterman ; Bingwei Lu [États-Unis] ; Yuzuru Imai [Japon]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-10-01.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Génétique.
English descriptors
- KwdEn :
Abstract
Missense mutations in leucine-rich repeat kinase 2 (LRRK2)/Dardarin gene, the product of which encodes a kinase with multiple domains, are known to cause autosomal dominant late onset Parkinson's disease (PD). In the current study, we report that the gene product LRRK2 directly phosphorylates the forkhead box transcription factor FoxO1 and enhances its transcriptional activity. This pathway was found to be conserved in Drosophila, as the Drosophila LRRK2 homolog (dLRRK) enhanced the neuronal toxicity of FoxO. Importantly, FoxO mutants that were resistant to LRRK2/dLRRK-induced phosphorylation suppressed this neurotoxicity. Moreover, we have determined that FoxO targets hid and bim in Drosophila and human, respectively, are responsible for the LRRK2/dLRRK-mediated cell death. These data suggest that the cell death molecules regulated by FoxO are key factors during the neurodegeneration in LRRK2-linked PD.
Url:
DOI: 10.1093/hmg/ddq289
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Park</name></author><author><name sortKey="Unterman, Terry" sort="Unterman, Terry" uniqKey="Unterman T" first="Terry" last="Unterman">Terry Unterman</name></author><author><name sortKey="Lu, Bingwei" sort="Lu, Bingwei" uniqKey="Lu B" first="Bingwei" last="Lu">Bingwei Lu</name></author><author><name sortKey="Imai, Yuzuru" sort="Imai, Yuzuru" uniqKey="Imai Y" first="Yuzuru" last="Imai">Yuzuru Imai</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:599578B603677F33CDBAA3AFE56AF80EAA6D0273</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1093/hmg/ddq289</idno><idno type="url">https://api-v5.istex.fr/document/599578B603677F33CDBAA3AFE56AF80EAA6D0273/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">002765</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">002765</idno><idno type="wicri:Area/Istex/Curation">002765</idno><idno type="wicri:Area/Istex/Checkpoint">000526</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Checkpoint">000526</idno><idno type="wicri:doubleKey">0964-6906:2010:Kanao T:activation:of:foxo</idno><idno type="wicri:Area/Main/Merge">001C54</idno><idno type="wicri:source">INIST</idno><idno type="RBID">Pascal:10-0449786</idno><idno type="wicri:Area/PascalFrancis/Corpus">000389</idno><idno type="wicri:Area/PascalFrancis/Curation">000888</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000397</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000397</idno><idno type="wicri:doubleKey">0964-6906:2010:Kanao T:activation:of:foxo</idno><idno type="wicri:Area/Main/Merge">001E87</idno><idno type="wicri:Area/Main/Curation">001B41</idno><idno type="wicri:Area/Main/Exploration">001B41</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila</title><author><name sortKey="Kanao, Tomoko" sort="Kanao, Tomoko" uniqKey="Kanao T" first="Tomoko" last="Kanao">Tomoko Kanao</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Venderova, Katerina" sort="Venderova, Katerina" uniqKey="Venderova K" first="Katerina" last="Venderova">Katerina Venderova</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S." last="Park">David S. Park</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Unterman, Terry" sort="Unterman, Terry" uniqKey="Unterman T" first="Terry" last="Unterman">Terry Unterman</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Lu, Bingwei" sort="Lu, Bingwei" uniqKey="Lu B" first="Bingwei" last="Lu">Bingwei Lu</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Geriatric Research, Education and Clinical Center/Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Imai, Yuzuru" sort="Imai, Yuzuru" uniqKey="Imai Y" first="Yuzuru" last="Imai">Yuzuru Imai</name><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Japon</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-10-01">2010-10-01</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">19</biblScope><biblScope unit="page" from="3747">3747</biblScope><biblScope unit="page" to="3758">3758</biblScope></imprint><idno type="ISSN">0964-6906</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Activation</term><term>Apoptosis</term><term>Drosophila melanogaster</term><term>Genetics</term><term>Neuron</term><term>Protein</term><term>Regulation(control)</term><term>Survival</term><term>Transcription factor FOXO</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Activation</term><term>Apoptose</term><term>Drosophila melanogaster</term><term>Facteur transcription FOXO</term><term>Génétique</term><term>Neurone</term><term>Protéine</term><term>Régulation</term><term>Survie</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract">Missense mutations in leucine-rich repeat kinase 2 (LRRK2)/Dardarin gene, the product of which encodes a kinase with multiple domains, are known to cause autosomal dominant late onset Parkinson's disease (PD). In the current study, we report that the gene product LRRK2 directly phosphorylates the forkhead box transcription factor FoxO1 and enhances its transcriptional activity. This pathway was found to be conserved in Drosophila, as the Drosophila LRRK2 homolog (dLRRK) enhanced the neuronal toxicity of FoxO. Importantly, FoxO mutants that were resistant to LRRK2/dLRRK-induced phosphorylation suppressed this neurotoxicity. Moreover, we have determined that FoxO targets hid and bim in Drosophila and human, respectively, are responsible for the LRRK2/dLRRK-mediated cell death. These data suggest that the cell death molecules regulated by FoxO are key factors during the neurodegeneration in LRRK2-linked PD.</div></front></TEI><affiliations><list><country><li>Japon</li><li>États-Unis</li></country><region><li>Californie</li></region></list><tree><noCountry><name sortKey="Kanao, Tomoko" sort="Kanao, Tomoko" uniqKey="Kanao T" first="Tomoko" last="Kanao">Tomoko Kanao</name><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S." last="Park">David S. Park</name><name sortKey="Unterman, Terry" sort="Unterman, Terry" uniqKey="Unterman T" first="Terry" last="Unterman">Terry Unterman</name><name sortKey="Venderova, Katerina" sort="Venderova, Katerina" uniqKey="Venderova K" first="Katerina" last="Venderova">Katerina Venderova</name></noCountry><country name="États-Unis"><region name="Californie"><name sortKey="Lu, Bingwei" sort="Lu, Bingwei" uniqKey="Lu B" first="Bingwei" last="Lu">Bingwei Lu</name></region><name sortKey="Lu, Bingwei" sort="Lu, Bingwei" uniqKey="Lu B" first="Bingwei" last="Lu">Bingwei Lu</name></country><country name="Japon"><noRegion><name sortKey="Imai, Yuzuru" sort="Imai, Yuzuru" uniqKey="Imai Y" first="Yuzuru" last="Imai">Yuzuru Imai</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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