Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease
Identifieur interne : 003120 ( Main/Corpus ); précédent : 003119; suivant : 003121Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease
Auteurs : Katerina Venderova ; Ghassan Kabbach ; Elizabeth Abdel-Messih ; Yi Zhang ; Robin J. Parks ; Yuzuru Imai ; Stephan Gehrke ; Johnny Ngsee ; Matthew J. Lavoie ; Ruth S. Slack ; Yong Rao ; Zhuohua Zhang ; Bingwei Lu ; M. Emdadul Haque ; David S. ParkSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2009-11-15.
Abstract
Mutations in the LRRK2 gene are the most common genetic cause of familial Parkinson's disease (PD). However, its physiological and pathological functions are unknown. Therefore, we generated several independent Drosophila lines carrying WT or mutant human LRRK2 (mutations in kinase, COR or LRR domains, resp.). Ectopic expression of WT or mutant LRRK2 in dopaminergic neurons caused their significant loss accompanied by complex age-dependent changes in locomotor activity. Overall, the ubiquitous expression of LRRK2 increased lifespan and fertility of the flies. However, these flies were more sensitive to rotenone. LRRK2 expression in the eye exacerbated retinal degeneration. Importantly, in double transgenic flies, various indices of the eye and dopaminergic survival were modified in a complex fashion by a concomitant expression of PINK1, DJ-1 or Parkin. This evidence suggests a genetic interaction between these PD-relevant genes.
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DOI: 10.1093/hmg/ddp394
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Parks</name><affiliation><mods:affiliation>Smyth Rd, Ottawa, Ontario, Canada K1H 8M5,</mods:affiliation></affiliation></author><author><name sortKey="Imai, Yuzuru" sort="Imai, Yuzuru" uniqKey="Imai Y" first="Yuzuru" last="Imai">Yuzuru Imai</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Gehrke, Stephan" sort="Gehrke, Stephan" uniqKey="Gehrke S" first="Stephan" last="Gehrke">Stephan Gehrke</name><affiliation><mods:affiliation>305, USA,</mods:affiliation></affiliation></author><author><name sortKey="Ngsee, Johnny" sort="Ngsee, Johnny" uniqKey="Ngsee J" first="Johnny" last="Ngsee">Johnny Ngsee</name><affiliation><mods:affiliation>Smyth Rd, Ottawa, Ontario, Canada K1H 8M5,</mods:affiliation></affiliation></author><author><name sortKey="Lavoie, Matthew J" sort="Lavoie, Matthew J" uniqKey="Lavoie M" first="Matthew J." last="Lavoie">Matthew J. Lavoie</name><affiliation><mods:affiliation>, USA,</mods:affiliation></affiliation></author><author><name sortKey="Slack, Ruth S" sort="Slack, Ruth S" uniqKey="Slack R" first="Ruth S." last="Slack">Ruth S. Slack</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Rao, Yong" sort="Rao, Yong" uniqKey="Rao Y" first="Yong" last="Rao">Yong Rao</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Zhang, Zhuohua" sort="Zhang, Zhuohua" uniqKey="Zhang Z" first="Zhuohua" last="Zhang">Zhuohua Zhang</name><affiliation><mods:affiliation>, USA</mods:affiliation></affiliation></author><author><name sortKey="Lu, Bingwei" sort="Lu, Bingwei" uniqKey="Lu B" first="Bingwei" last="Lu">Bingwei Lu</name><affiliation><mods:affiliation>305, USA,</mods:affiliation></affiliation></author><author><name sortKey="Haque, M Emdadul" sort="Haque, M Emdadul" uniqKey="Haque M" first="M. Emdadul" last="Haque">M. Emdadul Haque</name><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: dpark@uottawa.ca</mods:affiliation></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><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: dpark@uottawa.ca</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="2009-11-15">2009-11-15</date><biblScope unit="volume">18</biblScope><biblScope unit="issue">22</biblScope><biblScope unit="page" from="4390">4390</biblScope><biblScope unit="page" to="4404">4404</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">76F9BDDBCCE2EAA8E87F3A3D1BDD24AC475967A1</idno><idno type="DOI">10.1093/hmg/ddp394</idno><idno type="ArticleID">ddp394</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 in the LRRK2 gene are the most common genetic cause of familial Parkinson's disease (PD). However, its physiological and pathological functions are unknown. Therefore, we generated several independent Drosophila lines carrying WT or mutant human LRRK2 (mutations in kinase, COR or LRR domains, resp.). Ectopic expression of WT or mutant LRRK2 in dopaminergic neurons caused their significant loss accompanied by complex age-dependent changes in locomotor activity. Overall, the ubiquitous expression of LRRK2 increased lifespan and fertility of the flies. However, these flies were more sensitive to rotenone. LRRK2 expression in the eye exacerbated retinal degeneration. Importantly, in double transgenic flies, various indices of the eye and dopaminergic survival were modified in a complex fashion by a concomitant expression of PINK1, DJ-1 or Parkin. This evidence suggests a genetic interaction between these PD-relevant genes.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Katerina Venderova</name><affiliations><json:string>Ottawa Health Research Institute, Neuroscience Research Institute, 451 Smyth Rd, Ottawa, Ontario, Canada K1H 8M5,</json:string></affiliations></json:item><json:item><name>Ghassan Kabbach</name><affiliations><json:string>Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5,</json:string></affiliations></json:item><json:item><name>Elizabeth Abdel-Messih</name><affiliations><json:string>Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5,</json:string></affiliations></json:item><json:item><name>Yi Zhang</name><affiliations><json:string>Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5,</json:string></affiliations></json:item><json:item><name>Robin J. Parks</name><affiliations><json:string>Ottawa Health Research Institute, Neuroscience Research Institute, 451 Smyth Rd, Ottawa, Ontario, Canada K1H 8M5,</json:string></affiliations></json:item><json:item><name>Yuzuru Imai</name><affiliations><json:string>Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan,</json:string></affiliations></json:item><json:item><name>Stephan Gehrke</name><affiliations><json:string>Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA,</json:string></affiliations></json:item><json:item><name>Johnny Ngsee</name><affiliations><json:string>Ottawa Health Research Institute, Neuroscience Research Institute, 451 Smyth Rd, Ottawa, Ontario, Canada K1H 8M5,</json:string></affiliations></json:item><json:item><name>Matthew J. LaVoie</name><affiliations><json:string>Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA,</json:string></affiliations></json:item><json:item><name>Ruth S. Slack</name><affiliations><json:string>Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5,</json:string></affiliations></json:item><json:item><name>Yong Rao</name><affiliations><json:string>Center for Research in Neuroscience, University McGill, Montreal, Quebec, Canada H3G 1A4 and</json:string></affiliations></json:item><json:item><name>Zhuohua Zhang</name><affiliations><json:string>Burnham Institute for Medical Research, La Jolla, CA 92037, USA</json:string></affiliations></json:item><json:item><name>Bingwei Lu</name><affiliations><json:string>Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA,</json:string></affiliations></json:item><json:item><name>M. Emdadul Haque</name><affiliations><json:string>Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5,</json:string><json:string>E-mail: dpark@uottawa.ca</json:string></affiliations></json:item><json:item><name>David S. Park</name><affiliations><json:string>Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5,</json:string><json:string>E-mail: dpark@uottawa.ca</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 in the LRRK2 gene are the most common genetic cause of familial Parkinson's disease (PD). However, its physiological and pathological functions are unknown. Therefore, we generated several independent Drosophila lines carrying WT or mutant human LRRK2 (mutations in kinase, COR or LRR domains, resp.). Ectopic expression of WT or mutant LRRK2 in dopaminergic neurons caused their significant loss accompanied by complex age-dependent changes in locomotor activity. Overall, the ubiquitous expression of LRRK2 increased lifespan and fertility of the flies. However, these flies were more sensitive to rotenone. LRRK2 expression in the eye exacerbated retinal degeneration. Importantly, in double transgenic flies, various indices of the eye and dopaminergic survival were modified in a complex fashion by a concomitant expression of PINK1, DJ-1 or Parkin. This evidence suggests a genetic interaction between these PD-relevant genes.</abstract><qualityIndicators><score>7.608</score><pdfVersion>1.5</pdfVersion><pdfPageSize>612 x 797.953 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>1</keywordCount><abstractCharCount>942</abstractCharCount><pdfWordCount>7073</pdfWordCount><pdfCharCount>45216</pdfCharCount><pdfPageCount>15</pdfPageCount><abstractWordCount>134</abstractWordCount></qualityIndicators><title>Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease</title><genre><json:string>research-article</json:string></genre><host><volume>18</volume><pages><last>4404</last><first>4390</first></pages><issn><json:string>0964-6906</json:string></issn><issue>22</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>2009</publicationDate><copyrightDate>2009</copyrightDate><doi><json:string>10.1093/hmg/ddp394</json:string></doi><id>76F9BDDBCCE2EAA8E87F3A3D1BDD24AC475967A1</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/76F9BDDBCCE2EAA8E87F3A3D1BDD24AC475967A1/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/76F9BDDBCCE2EAA8E87F3A3D1BDD24AC475967A1/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/76F9BDDBCCE2EAA8E87F3A3D1BDD24AC475967A1/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease</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>2009-08-19</date></publicationStmt><notesStmt><note>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease</title><author><persName><forename type="first">Katerina</forename><surname>Venderova</surname></persName><note type="biography">The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</note><affiliation>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</affiliation><affiliation>Smyth Rd, Ottawa, Ontario, Canada K1H 8M5,</affiliation></author><author><persName><forename type="first">Ghassan</forename><surname>Kabbach</surname></persName><note type="biography">The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</note><affiliation>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</affiliation><affiliation></affiliation></author><author><persName><forename type="first">Elizabeth</forename><surname>Abdel-Messih</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Yi</forename><surname>Zhang</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Robin J.</forename><surname>Parks</surname></persName><affiliation>Smyth Rd, Ottawa, Ontario, Canada K1H 8M5,</affiliation></author><author><persName><forename type="first">Yuzuru</forename><surname>Imai</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Stephan</forename><surname>Gehrke</surname></persName><affiliation>305, USA,</affiliation></author><author><persName><forename type="first">Johnny</forename><surname>Ngsee</surname></persName><affiliation>Smyth Rd, Ottawa, Ontario, Canada K1H 8M5,</affiliation></author><author><persName><forename type="first">Matthew J.</forename><surname>LaVoie</surname></persName><affiliation>, USA,</affiliation></author><author><persName><forename type="first">Ruth S.</forename><surname>Slack</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Yong</forename><surname>Rao</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Zhuohua</forename><surname>Zhang</surname></persName><affiliation>, USA</affiliation></author><author><persName><forename type="first">Bingwei</forename><surname>Lu</surname></persName><affiliation>305, USA,</affiliation></author><author><persName><forename type="first">M. Emdadul</forename><surname>Haque</surname></persName><email>dpark@uottawa.ca</email><affiliation></affiliation></author><author><persName><forename type="first">David S.</forename><surname>Park</surname></persName><email>dpark@uottawa.ca</email><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="2009-11-15"></date><biblScope unit="volume">18</biblScope><biblScope unit="issue">22</biblScope><biblScope unit="page" from="4390">4390</biblScope><biblScope unit="page" to="4404">4404</biblScope></imprint></monogr><idno type="istex">76F9BDDBCCE2EAA8E87F3A3D1BDD24AC475967A1</idno><idno type="DOI">10.1093/hmg/ddp394</idno><idno type="ArticleID">ddp394</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2009-08-19</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Mutations in the LRRK2 gene are the most common genetic cause of familial Parkinson's disease (PD). However, its physiological and pathological functions are unknown. Therefore, we generated several independent Drosophila lines carrying WT or mutant human LRRK2 (mutations in kinase, COR or LRR domains, resp.). Ectopic expression of WT or mutant LRRK2 in dopaminergic neurons caused their significant loss accompanied by complex age-dependent changes in locomotor activity. Overall, the ubiquitous expression of LRRK2 increased lifespan and fertility of the flies. However, these flies were more sensitive to rotenone. LRRK2 expression in the eye exacerbated retinal degeneration. Importantly, in double transgenic flies, various indices of the eye and dopaminergic survival were modified in a complex fashion by a concomitant expression of PINK1, DJ-1 or Parkin. This evidence suggests a genetic interaction between these PD-relevant genes.</p></abstract></profileDesc><revisionDesc><change when="2009-08-19">Created</change><change when="2009-11-15">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/76F9BDDBCCE2EAA8E87F3A3D1BDD24AC475967A1/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/ddp394</article-id><article-id pub-id-type="publisher-id">ddp394</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title><italic>Leucine-rich repeat kinase 2</italic> interacts with <italic>Parkin, DJ-1</italic> and <italic>PINK-1</italic> in a <italic>Drosophila melanogaster</italic> model of Parkinson's disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Venderova</surname><given-names>Katerina</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="fn" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Kabbach</surname><given-names>Ghassan</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="fn" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Abdel-Messih</surname><given-names>Elizabeth</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Yi</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Parks</surname><given-names>Robin J.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Imai</surname><given-names>Yuzuru</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Gehrke</surname><given-names>Stephan</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Ngsee</surname><given-names>Johnny</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>LaVoie</surname><given-names>Matthew J.</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Slack</surname><given-names>Ruth S.</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Rao</surname><given-names>Yong</given-names></name><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Zhuohua</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Lu</surname><given-names>Bingwei</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Haque</surname><given-names>M. Emdadul</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>David S.</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><institution>Ottawa Health Research Institute, Neuroscience Research Institute</institution>, <addr-line>451 Smyth Rd, Ottawa, Ontario</addr-line>, <country>Canada</country> <addr-line>K1H 8M5</addr-line>,</aff><aff id="af2"><label>2</label><addr-line>Department of Cellular and Molecular Medicine</addr-line>, <institution>University of Ottawa</institution>, <addr-line>451 Smyth Road, Ottawa, Ontario</addr-line>, <country>Canada</country> <addr-line>K1H 8M5</addr-line>,</aff><aff id="af3"><label>3</label><institution>Institute of Development, Aging and Cancer, Tohoku University</institution>, <addr-line>Sendai 980-8575</addr-line>, <country>Japan</country>,</aff><aff id="af4"><label>4</label><addr-line>Department of Pathology</addr-line>, <institution>Stanford University School of Medicine</institution>, <addr-line>Stanford, CA 94305</addr-line>, <country>USA</country>,</aff><aff id="af5"><label>5</label><institution>Brigham and Women's Hospital and Harvard Medical School</institution>, <addr-line>Boston, MA 02115</addr-line>, <country>USA</country>,</aff><aff id="af6"><label>6</label><institution>Center for Research in Neuroscience, University McGill</institution>, <addr-line>Montreal, Quebec</addr-line>, <country>Canada</country> <addr-line>H3G 1A4</addr-line> and</aff><aff id="af7"><label>7</label><institution>Burnham Institute for Medical Research</institution>, <addr-line>La Jolla, CA 92037</addr-line>, <country>USA</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed. Tel: <phone>+1 6135625800 extn 8816</phone>; Fax: <fax>+1 6135625403</fax>; Email: <email>dpark@uottawa.ca</email> (D.S.P.); <email>ehaque@uottawa.ca</email> (M.E.H.)</corresp><fn id="FN1"><label>†</label><p>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</p></fn></author-notes><pub-date pub-type="ppub"><day>15</day><month>11</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>19</day><month>8</month><year>2009</year></pub-date><volume>18</volume><issue>22</issue><fpage>4390</fpage><lpage>4404</lpage><history><date date-type="received"><day>23</day><month>7</month><year>2009</year></date><date date-type="rev-recd"><day>23</day><month>7</month><year>2009</year></date><date date-type="accepted"><day>13</day><month>8</month><year>2009</year></date></history><copyright-statement>© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2009</copyright-year><abstract><p>Mutations in the <italic>LRRK2</italic> gene are the most common genetic cause of familial Parkinson's disease (PD). However, its physiological and pathological functions are unknown. Therefore, we generated several independent <italic>Drosophila</italic> lines carrying WT or mutant human <italic>LRRK2</italic> (mutations in kinase, COR or LRR domains, resp.). Ectopic expression of WT or mutant <italic>LRRK2</italic> in dopaminergic neurons caused their significant loss accompanied by complex age-dependent changes in locomotor activity. Overall, the ubiquitous expression of <italic>LRRK2</italic> increased lifespan and fertility of the flies. However, these flies were more sensitive to rotenone. <italic>LRRK2</italic> expression in the eye exacerbated retinal degeneration. Importantly, in double transgenic flies, various indices of the eye and dopaminergic survival were modified in a complex fashion by a concomitant expression of <italic>PINK1, DJ-1</italic> or <italic>Parkin</italic>. This evidence suggests a genetic interaction between these PD-relevant genes.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Katerina</namePart><namePart type="family">Venderova</namePart><affiliation>Smyth Rd, Ottawa, Ontario, Canada K1H 8M5,</affiliation><description>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ghassan</namePart><namePart type="family">Kabbach</namePart><affiliation></affiliation><description>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Elizabeth</namePart><namePart type="family">Abdel-Messih</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yi</namePart><namePart type="family">Zhang</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Robin J.</namePart><namePart type="family">Parks</namePart><affiliation>Smyth Rd, Ottawa, Ontario, Canada K1H 8M5,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yuzuru</namePart><namePart type="family">Imai</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stephan</namePart><namePart type="family">Gehrke</namePart><affiliation>305, USA,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Johnny</namePart><namePart type="family">Ngsee</namePart><affiliation>Smyth Rd, Ottawa, Ontario, Canada K1H 8M5,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Matthew J.</namePart><namePart type="family">LaVoie</namePart><affiliation>, USA,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ruth S.</namePart><namePart type="family">Slack</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yong</namePart><namePart type="family">Rao</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Zhuohua</namePart><namePart type="family">Zhang</namePart><affiliation>, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Bingwei</namePart><namePart type="family">Lu</namePart><affiliation>305, USA,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M. Emdadul</namePart><namePart type="family">Haque</namePart><affiliation></affiliation><affiliation>E-mail: dpark@uottawa.ca</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David S.</namePart><namePart type="family">Park</namePart><affiliation></affiliation><affiliation>E-mail: dpark@uottawa.ca</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">2009-11-15</dateIssued><dateCreated encoding="w3cdtf">2009-08-19</dateCreated><copyrightDate encoding="w3cdtf">2009</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 in the LRRK2 gene are the most common genetic cause of familial Parkinson's disease (PD). However, its physiological and pathological functions are unknown. Therefore, we generated several independent Drosophila lines carrying WT or mutant human LRRK2 (mutations in kinase, COR or LRR domains, resp.). Ectopic expression of WT or mutant LRRK2 in dopaminergic neurons caused their significant loss accompanied by complex age-dependent changes in locomotor activity. Overall, the ubiquitous expression of LRRK2 increased lifespan and fertility of the flies. However, these flies were more sensitive to rotenone. LRRK2 expression in the eye exacerbated retinal degeneration. Importantly, in double transgenic flies, various indices of the eye and dopaminergic survival were modified in a complex fashion by a concomitant expression of PINK1, DJ-1 or Parkin. This evidence suggests a genetic interaction between these PD-relevant genes.</abstract><note type="footnotes">The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</note><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>2009</date><detail type="volume"><caption>vol.</caption><number>18</number></detail><detail type="issue"><caption>no.</caption><number>22</number></detail><extent unit="pages"><start>4390</start><end>4404</end></extent></part></relatedItem><identifier type="istex">76F9BDDBCCE2EAA8E87F3A3D1BDD24AC475967A1</identifier><identifier type="DOI">10.1093/hmg/ddp394</identifier><identifier type="ArticleID">ddp394</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2009. 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