A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in -synuclein transgenic C. elegans
Identifieur interne : 000C15 ( Main/Exploration ); précédent : 000C14; suivant : 000C16A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in -synuclein transgenic C. elegans
Auteurs : Tomoki Kuwahara ; Akihiko Koyama ; Shingo Koyama ; Sawako Yoshina ; Chang-Hong Ren ; Takeo Kato ; Shohei Mitani ; Takeshi Iwatsubo [Japon]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2008-10-01.
Abstract
Mutations or multiplications in -synuclein gene cause familial forms of Parkinson disease or dementia with Lewy bodies (LB), and the deposition of wild-type -synuclein as LB occurs as a hallmark lesion of these disorders, collectively referred to as synucleinopathies, implicating -synuclein in the pathogenesis of synucleinopathy. To identify modifier genes of -synuclein-induced neurotoxicity, we conducted an RNAi screen in transgenic C. elegans (Tg worms) that overexpress human -synuclein in a pan-neuronal manner. To enhance the RNAi effect in neurons, we crossed -synuclein Tg worms with an RNAi-enhanced mutant eri-1 strain. We tested RNAi of 1673 genes related to nervous system or synaptic functions, and identified 10 genes that, upon knockdown, caused severe growth/motor abnormalities selectively in -synuclein Tg worms. Among these were four genes (i.e. apa-2, aps-2, eps-8 and rab-7) related to the endocytic pathway, including two subunits of AP-2 complex. Consistent with the results by RNAi, crossing -synuclein Tg worms with an aps-2 mutant resulted in severe growth arrest and motor dysfunction. -Synuclein Tg worms displayed a decreased touch sensitivity upon RNAi of genes involved in synaptic vesicle endocytosis, and they also showed impaired neuromuscular transmission, suggesting that overexpression of -synuclein caused a failure in uptake or recycling of synaptic vesicles. Furthermore, knockdown of apa-2, an AP-2 subunit, caused an accumulation of phosphorylated -synuclein in neuronal cell bodies, mimicking synucleinopathy. Collectively, these findings raise a novel pathogenic link between endocytic pathway and -synuclein-induced neurotoxicity in synucleinopathy.
Url:
DOI: 10.1093/hmg/ddn198
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T" first="Takeo" last="Kato">Takeo Kato</name></author><author><name sortKey="Mitani, Shohei" sort="Mitani, Shohei" uniqKey="Mitani S" first="Shohei" last="Mitani">Shohei Mitani</name></author><author><name sortKey="Iwatsubo, Takeshi" sort="Iwatsubo, Takeshi" uniqKey="Iwatsubo T" first="Takeshi" last="Iwatsubo">Takeshi Iwatsubo</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:59D6009DD0C08213ADDB51395A3CCAA4F927F36E</idno><date when="2008" year="2008">2008</date><idno type="doi">10.1093/hmg/ddn198</idno><idno type="url">https://api.istex.fr/document/59D6009DD0C08213ADDB51395A3CCAA4F927F36E/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">002582</idno><idno type="wicri:Area/Main/Curation">002245</idno><idno type="wicri:Area/Main/Exploration">000C15</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in -synuclein 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code="syntax">???</wicri:noCountry></affiliation><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></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="2008-10-01">2008-10-01</date><biblScope unit="volume">17</biblScope><biblScope unit="issue">19</biblScope><biblScope unit="page" from="2997">2997</biblScope><biblScope unit="page" to="3009">3009</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">59D6009DD0C08213ADDB51395A3CCAA4F927F36E</idno><idno type="DOI">10.1093/hmg/ddn198</idno><idno type="ArticleID">ddn198</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">Mutations or multiplications in -synuclein gene cause familial forms of Parkinson disease or dementia with Lewy bodies (LB), and the deposition of wild-type -synuclein as LB occurs as a hallmark lesion of these disorders, collectively referred to as synucleinopathies, implicating -synuclein in the pathogenesis of synucleinopathy. To identify modifier genes of -synuclein-induced neurotoxicity, we conducted an RNAi screen in transgenic C. elegans (Tg worms) that overexpress human -synuclein in a pan-neuronal manner. To enhance the RNAi effect in neurons, we crossed -synuclein Tg worms with an RNAi-enhanced mutant eri-1 strain. We tested RNAi of 1673 genes related to nervous system or synaptic functions, and identified 10 genes that, upon knockdown, caused severe growth/motor abnormalities selectively in -synuclein Tg worms. Among these were four genes (i.e. apa-2, aps-2, eps-8 and rab-7) related to the endocytic pathway, including two subunits of AP-2 complex. Consistent with the results by RNAi, crossing -synuclein Tg worms with an aps-2 mutant resulted in severe growth arrest and motor dysfunction. -Synuclein Tg worms displayed a decreased touch sensitivity upon RNAi of genes involved in synaptic vesicle endocytosis, and they also showed impaired neuromuscular transmission, suggesting that overexpression of -synuclein caused a failure in uptake or recycling of synaptic vesicles. Furthermore, knockdown of apa-2, an AP-2 subunit, caused an accumulation of phosphorylated -synuclein in neuronal cell bodies, mimicking synucleinopathy. Collectively, these findings raise a novel pathogenic link between endocytic pathway and -synuclein-induced neurotoxicity in synucleinopathy.</div></front></TEI><affiliations><list><country><li>Japon</li></country></list><tree><noCountry><name sortKey="Kato, Takeo" sort="Kato, Takeo" uniqKey="Kato T" first="Takeo" last="Kato">Takeo Kato</name><name sortKey="Koyama, Akihiko" sort="Koyama, Akihiko" uniqKey="Koyama A" first="Akihiko" last="Koyama">Akihiko Koyama</name><name sortKey="Koyama, Shingo" sort="Koyama, Shingo" uniqKey="Koyama S" first="Shingo" last="Koyama">Shingo Koyama</name><name sortKey="Kuwahara, Tomoki" sort="Kuwahara, Tomoki" uniqKey="Kuwahara T" first="Tomoki" last="Kuwahara">Tomoki Kuwahara</name><name sortKey="Mitani, Shohei" sort="Mitani, Shohei" uniqKey="Mitani S" first="Shohei" last="Mitani">Shohei Mitani</name><name sortKey="Ren, Chang Hong" sort="Ren, Chang Hong" uniqKey="Ren C" first="Chang-Hong" last="Ren">Chang-Hong Ren</name><name sortKey="Yoshina, Sawako" sort="Yoshina, Sawako" uniqKey="Yoshina S" first="Sawako" last="Yoshina">Sawako Yoshina</name></noCountry><country name="Japon"><noRegion><name sortKey="Iwatsubo, Takeshi" sort="Iwatsubo, Takeshi" uniqKey="Iwatsubo T" first="Takeshi" last="Iwatsubo">Takeshi Iwatsubo</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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