A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in -synuclein transgenic C. elegans
Identifieur interne : 002582 ( Main/Corpus ); précédent : 002581; suivant : 002583A 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 IwatsuboSource :
- 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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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in -synuclein transgenic C. elegans</title><author><name sortKey="Kuwahara, Tomoki" sort="Kuwahara, Tomoki" uniqKey="Kuwahara T" first="Tomoki" last="Kuwahara">Tomoki Kuwahara</name><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Koyama, Akihiko" sort="Koyama, Akihiko" uniqKey="Koyama A" first="Akihiko" last="Koyama">Akihiko Koyama</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Koyama, Shingo" sort="Koyama, Shingo" uniqKey="Koyama S" first="Shingo" last="Koyama">Shingo Koyama</name><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Yoshina, Sawako" sort="Yoshina, Sawako" uniqKey="Yoshina S" first="Sawako" last="Yoshina">Sawako Yoshina</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Ren, Chang Hong" sort="Ren, Chang Hong" uniqKey="Ren C" first="Chang-Hong" last="Ren">Chang-Hong Ren</name><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Kato, Takeo" sort="Kato, Takeo" uniqKey="Kato T" first="Takeo" last="Kato">Takeo Kato</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Mitani, Shohei" sort="Mitani, Shohei" uniqKey="Mitani S" first="Shohei" last="Mitani">Shohei Mitani</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Iwatsubo, Takeshi" sort="Iwatsubo, Takeshi" uniqKey="Iwatsubo T" first="Takeshi" last="Iwatsubo">Takeshi Iwatsubo</name><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: iwatsubo@mol.f.u-tokyo.ac.jp</mods:affiliation></affiliation></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></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in -synuclein transgenic C. elegans</title><author><name sortKey="Kuwahara, Tomoki" sort="Kuwahara, Tomoki" uniqKey="Kuwahara T" first="Tomoki" last="Kuwahara">Tomoki Kuwahara</name><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Koyama, Akihiko" sort="Koyama, Akihiko" uniqKey="Koyama A" first="Akihiko" last="Koyama">Akihiko Koyama</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Koyama, Shingo" sort="Koyama, Shingo" uniqKey="Koyama S" first="Shingo" last="Koyama">Shingo Koyama</name><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Yoshina, Sawako" sort="Yoshina, Sawako" uniqKey="Yoshina S" first="Sawako" last="Yoshina">Sawako Yoshina</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Ren, Chang Hong" sort="Ren, Chang Hong" uniqKey="Ren C" first="Chang-Hong" last="Ren">Chang-Hong Ren</name><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Kato, Takeo" sort="Kato, Takeo" uniqKey="Kato T" first="Takeo" last="Kato">Takeo Kato</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Mitani, Shohei" sort="Mitani, Shohei" uniqKey="Mitani S" first="Shohei" last="Mitani">Shohei Mitani</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Iwatsubo, Takeshi" sort="Iwatsubo, Takeshi" uniqKey="Iwatsubo T" first="Takeshi" last="Iwatsubo">Takeshi Iwatsubo</name><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: iwatsubo@mol.f.u-tokyo.ac.jp</mods:affiliation></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><istex><corpusName>oup</corpusName><author><json:item><name>Tomoki Kuwahara</name><affiliations><json:string>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences</json:string><json:string>Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan</json:string></affiliations></json:item><json:item><name>Akihiko Koyama</name><affiliations><json:string>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences</json:string></affiliations></json:item><json:item><name>Shingo Koyama</name><affiliations><json:string>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences</json:string><json:string>Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, Yamagata, Japan</json:string></affiliations></json:item><json:item><name>Sawako Yoshina</name><affiliations><json:string>Department of Physiology, School of Medicine, Tokyo Womens Medical University, Tokyo, Japan</json:string></affiliations></json:item><json:item><name>Chang-Hong Ren</name><affiliations><json:string>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences</json:string><json:string>Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, Yamagata, Japan</json:string></affiliations></json:item><json:item><name>Takeo Kato</name><affiliations><json:string>Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, Yamagata, Japan</json:string></affiliations></json:item><json:item><name>Shohei Mitani</name><affiliations><json:string>Department of Physiology, School of Medicine, Tokyo Womens Medical University, Tokyo, Japan</json:string></affiliations></json:item><json:item><name>Takeshi Iwatsubo</name><affiliations><json:string>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences</json:string><json:string>Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan</json:string><json:string>E-mail: iwatsubo@mol.f.u-tokyo.ac.jp</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>ARTICLES</value></json:item></subject><language><json:string>eng</json:string></language><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.</abstract><qualityIndicators><score>7.844</score><pdfVersion>1.2</pdfVersion><pdfPageSize>612 x 797.953 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>1</keywordCount><abstractCharCount>1697</abstractCharCount><pdfWordCount>8076</pdfWordCount><pdfCharCount>53106</pdfCharCount><pdfPageCount>13</pdfPageCount><abstractWordCount>237</abstractWordCount></qualityIndicators><title>A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in -synuclein transgenic C. elegans</title><genre><json:string>research-article</json:string></genre><host><volume>17</volume><pages><last>3009</last><first>2997</first></pages><issn><json:string>0964-6906</json:string></issn><issue>19</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2083</json:string></eissn><title>Human Molecular Genetics</title></host><categories><wos><json:string>BIOCHEMISTRY & MOLECULAR BIOLOGY</json:string><json:string>GENETICS & HEREDITY</json:string></wos></categories><publicationDate>2008</publicationDate><copyrightDate>2008</copyrightDate><doi><json:string>10.1093/hmg/ddn198</json:string></doi><id>59D6009DD0C08213ADDB51395A3CCAA4F927F36E</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/59D6009DD0C08213ADDB51395A3CCAA4F927F36E/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/59D6009DD0C08213ADDB51395A3CCAA4F927F36E/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/59D6009DD0C08213ADDB51395A3CCAA4F927F36E/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in -synuclein transgenic C. elegans</title><respStmt xml:id="ISTEX-API" resp="Références bibliographiques récupérées via GROBID" name="ISTEX-API (INIST-CNRS)"></respStmt></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>OUP</p></availability><date>2008-07-09</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in -synuclein transgenic C. elegans</title><author><persName><forename type="first">Tomoki</forename><surname>Kuwahara</surname></persName><affiliation></affiliation><affiliation></affiliation></author><author><persName><forename type="first">Akihiko</forename><surname>Koyama</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Shingo</forename><surname>Koyama</surname></persName><affiliation></affiliation><affiliation></affiliation></author><author><persName><forename type="first">Sawako</forename><surname>Yoshina</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Chang-Hong</forename><surname>Ren</surname></persName><affiliation></affiliation><affiliation></affiliation></author><author><persName><forename type="first">Takeo</forename><surname>Kato</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Shohei</forename><surname>Mitani</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Takeshi</forename><surname>Iwatsubo</surname></persName><email>iwatsubo@mol.f.u-tokyo.ac.jp</email><affiliation></affiliation><affiliation></affiliation></author></analytic><monogr><title level="j">Human Molecular Genetics</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="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></monogr><idno type="istex">59D6009DD0C08213ADDB51395A3CCAA4F927F36E</idno><idno type="DOI">10.1093/hmg/ddn198</idno><idno type="ArticleID">ddn198</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2008-07-09</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>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.</p></abstract></profileDesc><revisionDesc><change when="2008-07-09">Created</change><change when="2008-10-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-15">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/59D6009DD0C08213ADDB51395A3CCAA4F927F36E/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-id journal-id-type="hwp">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/hmg/ddn198</article-id><article-id pub-id-type="publisher-id">ddn198</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in α-synuclein transgenic <italic>C</italic>. <italic>elegans</italic></article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Kuwahara</surname><given-names>Tomoki</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Koyama</surname><given-names>Akihiko</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Koyama</surname><given-names>Shingo</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Yoshina</surname><given-names>Sawako</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Ren</surname><given-names>Chang-Hong</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Kato</surname><given-names>Takeo</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Mitani</surname><given-names>Shohei</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Iwatsubo</surname><given-names>Takeshi</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences</addr-line></aff><aff id="af2"><label>2</label><addr-line>Department of Neuropathology, Graduate School of Medicine</addr-line>, <institution>University of Tokyo</institution>, <addr-line>Tokyo</addr-line>, <country>Japan</country></aff><aff id="af3"><label>3</label><addr-line>Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine</addr-line>, <institution>Yamagata University</institution>, <addr-line>Yamagata</addr-line>, <country>Japan</country></aff><aff id="af4"><label>4</label><addr-line>Department of Physiology</addr-line>, <institution>School of Medicine, Tokyo Women’s Medical University</institution>, <addr-line>Tokyo</addr-line>, <country>Japan</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: <addr-line>Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences</addr-line>, <institution>University of Tokyo</institution>, <addr-line>7-3-1 Hongo Bunkyoku, Tokyo 113-0033</addr-line>, <country>Japan</country>. Tel: <phone>+81 358414877</phone>; Fax: <fax>+81 358414708</fax>; Email: <email>iwatsubo@mol.f.u-tokyo.ac.jp</email></corresp></author-notes><pub-date pub-type="ppub"><day>1</day><month>10</month><year>2008</year></pub-date><pub-date pub-type="epub"><day>9</day><month>7</month><year>2008</year></pub-date><volume>17</volume><issue>19</issue><fpage>2997</fpage><lpage>3009</lpage><history><date date-type="received"><day>6</day><month>5</month><year>2008</year></date><date date-type="accepted"><day>8</day><month>7</month><year>2008</year></date></history><copyright-statement>© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2008</copyright-year><abstract><p>Mutations or multiplications in α-synuclein gene cause familial forms of Parkinson disease or dementia with Lewy bodies (LB), and the deposition of wild-type α-synuclein as LB occurs as a hallmark lesion of these disorders, collectively referred to as synucleinopathies, implicating α-synuclein in the pathogenesis of synucleinopathy. To identify modifier genes of α-synuclein-induced neurotoxicity, we conducted an RNAi screen in transgenic <italic>C</italic>. <italic>elegans</italic> (Tg worms) that overexpress human α-synuclein in a pan-neuronal manner. To enhance the RNAi effect in neurons, we crossed α-synuclein Tg worms with an RNAi-enhanced mutant <italic>eri-1</italic> 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 α-synuclein Tg worms. Among these were four genes (i.e. <italic>apa-2, aps-2, eps-8</italic> and <italic>rab-7</italic>) related to the endocytic pathway, including two subunits of AP-2 complex. Consistent with the results by RNAi, crossing α-synuclein Tg worms with an <italic>aps-2</italic> mutant resulted in severe growth arrest and motor dysfunction. α-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 α-synuclein caused a failure in uptake or recycling of synaptic vesicles. Furthermore, knockdown of <italic>apa-2</italic>, an AP-2 subunit, caused an accumulation of phosphorylated α-synuclein in neuronal cell bodies, mimicking synucleinopathy. Collectively, these findings raise a novel pathogenic link between endocytic pathway and α-synuclein-induced neurotoxicity in synucleinopathy.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in -synuclein transgenic C. elegans</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in -synuclein transgenic C. elegans</title></titleInfo><name type="personal"><namePart type="given">Tomoki</namePart><namePart type="family">Kuwahara</namePart><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Akihiko</namePart><namePart type="family">Koyama</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Shingo</namePart><namePart type="family">Koyama</namePart><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sawako</namePart><namePart type="family">Yoshina</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Chang-Hong</namePart><namePart type="family">Ren</namePart><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Takeo</namePart><namePart type="family">Kato</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Shohei</namePart><namePart type="family">Mitani</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Takeshi</namePart><namePart type="family">Iwatsubo</namePart><affiliation></affiliation><affiliation></affiliation><affiliation>E-mail: iwatsubo@mol.f.u-tokyo.ac.jp</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2008-10-01</dateIssued><dateCreated encoding="w3cdtf">2008-07-09</dateCreated><copyrightDate encoding="w3cdtf">2008</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><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.</abstract><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><part><date>2008</date><detail type="volume"><caption>vol.</caption><number>17</number></detail><detail type="issue"><caption>no.</caption><number>19</number></detail><extent unit="pages"><start>2997</start><end>3009</end></extent></part></relatedItem><identifier type="istex">59D6009DD0C08213ADDB51395A3CCAA4F927F36E</identifier><identifier type="DOI">10.1093/hmg/ddn198</identifier><identifier type="ArticleID">ddn198</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2008. 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