Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio)
Identifieur interne : 001937 ( Main/Corpus ); précédent : 001936; suivant : 001938Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio)
Auteurs : Laura Flinn ; Heather Mortiboys ; Katrin Volkmann ; Reinhard W. Köster ; Phillip W. Ingham ; Oliver BandmannSource :
- Brain [ 0006-8950 ] ; 2009-06.
Abstract
Currently, only symptomatic therapy is available for Parkinson's disease. The zebrafish is a vertebrate animal model ideally suited for high throughput compound screening to identify disease-modifying compounds for Parkinson's disease. We have developed a zebrafish model for Parkin deficiency, the most commonly mutated gene in early onset Parkinson's disease. The zebrafish Parkin protein is 62% identical to its human counterpart with 78% identity in functionally relevant regions. The parkin gene is expressed throughout zebrafish development and ubiquitously in adult zebrafish tissue. Abrogation of Parkin activity leads to a significant decrease in the number of ascending dopaminergic neurons in the posterior tuberculum (homologous to the substantia nigra in humans), an effect enhanced by exposure to MPP+. Both light microscopic analysis and staining with the pan-neuronal marker HuC confirmed that this loss of dopaminergic neurons is not due to general impairment of brain development. Neither serotonergic nor motor neurons were affected, further emphasizing that the effect of parkin knockdown appears to be specific for dopaminergic neurons. Notably, parkin knockdown zebrafish embryos also develop specific reduction in the activity of the mitochondrial respiratory chain complex I, making this the first vertebrate model to share both important pathogenic mechanisms (i.e. complex I deficiency) and the pathological hallmark (i.e. dopaminergic cell loss) with human parkin-mutant patients. The zebrafish model is thus ideally suited for future drug screens and other studies investigating the functional mechanisms underlying neuronal cell death in early onset Parkinson's Disease. Additional electron microscopy studies revealed electron dense material in the t-tubules within the muscle tissue of parkin knockdown zebrafish. T-tubules are rich in L-type calcium channels, therefore our work might also provide a tentative link between genetically determined early onset Parkinson's disease and recent studies attributing an important role to these L-type calcium channels in late onset sporadic Parkinson's disease.
Url:
DOI: 10.1093/brain/awp108
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Köster</name><affiliation><mods:affiliation>3 Helmholtz-Centre Munich, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg-Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Ingham, Phillip W" sort="Ingham, Phillip W" uniqKey="Ingham P" first="Phillip W." last="Ingham">Phillip W. Ingham</name><affiliation><mods:affiliation>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</mods:affiliation></affiliation></author><author><name sortKey="Bandmann, Oliver" sort="Bandmann, Oliver" uniqKey="Bandmann O" first="Oliver" last="Bandmann">Oliver Bandmann</name><affiliation><mods:affiliation>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</mods:affiliation></affiliation><affiliation><mods:affiliation>2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: o.bandmann@sheffield.ac.uk</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:403604A6D24E1E920E1E90A5F8179825BBADC1ED</idno><date when="2009" year="2009">2009</date><idno type="doi">10.1093/brain/awp108</idno><idno type="url">https://api.istex.fr/document/403604A6D24E1E920E1E90A5F8179825BBADC1ED/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">001937</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio)</title><author><name sortKey="Flinn, Laura" sort="Flinn, Laura" uniqKey="Flinn L" first="Laura" last="Flinn">Laura Flinn</name><affiliation><mods:affiliation>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</mods:affiliation></affiliation><affiliation><mods:affiliation>2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</mods:affiliation></affiliation></author><author><name sortKey="Mortiboys, Heather" sort="Mortiboys, Heather" uniqKey="Mortiboys H" first="Heather" last="Mortiboys">Heather Mortiboys</name><affiliation><mods:affiliation>2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</mods:affiliation></affiliation></author><author><name sortKey="Volkmann, Katrin" sort="Volkmann, Katrin" uniqKey="Volkmann K" first="Katrin" last="Volkmann">Katrin Volkmann</name><affiliation><mods:affiliation>3 Helmholtz-Centre Munich, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg-Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Koster, Reinhard W" sort="Koster, Reinhard W" uniqKey="Koster R" first="Reinhard W." last="Köster">Reinhard W. Köster</name><affiliation><mods:affiliation>3 Helmholtz-Centre Munich, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg-Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Ingham, Phillip W" sort="Ingham, Phillip W" uniqKey="Ingham P" first="Phillip W." last="Ingham">Phillip W. Ingham</name><affiliation><mods:affiliation>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</mods:affiliation></affiliation></author><author><name sortKey="Bandmann, Oliver" sort="Bandmann, Oliver" uniqKey="Bandmann O" first="Oliver" last="Bandmann">Oliver Bandmann</name><affiliation><mods:affiliation>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</mods:affiliation></affiliation><affiliation><mods:affiliation>2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: o.bandmann@sheffield.ac.uk</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Brain</title><idno type="ISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2009-06">2009-06</date><biblScope unit="volume">132</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="1613">1613</biblScope><biblScope unit="page" to="1623">1623</biblScope></imprint><idno type="ISSN">0006-8950</idno></series><idno type="istex">403604A6D24E1E920E1E90A5F8179825BBADC1ED</idno><idno type="DOI">10.1093/brain/awp108</idno><idno type="ArticleID">awp108</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-8950</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Currently, only symptomatic therapy is available for Parkinson's disease. The zebrafish is a vertebrate animal model ideally suited for high throughput compound screening to identify disease-modifying compounds for Parkinson's disease. We have developed a zebrafish model for Parkin deficiency, the most commonly mutated gene in early onset Parkinson's disease. The zebrafish Parkin protein is 62% identical to its human counterpart with 78% identity in functionally relevant regions. The parkin gene is expressed throughout zebrafish development and ubiquitously in adult zebrafish tissue. Abrogation of Parkin activity leads to a significant decrease in the number of ascending dopaminergic neurons in the posterior tuberculum (homologous to the substantia nigra in humans), an effect enhanced by exposure to MPP+. Both light microscopic analysis and staining with the pan-neuronal marker HuC confirmed that this loss of dopaminergic neurons is not due to general impairment of brain development. Neither serotonergic nor motor neurons were affected, further emphasizing that the effect of parkin knockdown appears to be specific for dopaminergic neurons. Notably, parkin knockdown zebrafish embryos also develop specific reduction in the activity of the mitochondrial respiratory chain complex I, making this the first vertebrate model to share both important pathogenic mechanisms (i.e. complex I deficiency) and the pathological hallmark (i.e. dopaminergic cell loss) with human parkin-mutant patients. The zebrafish model is thus ideally suited for future drug screens and other studies investigating the functional mechanisms underlying neuronal cell death in early onset Parkinson's Disease. Additional electron microscopy studies revealed electron dense material in the t-tubules within the muscle tissue of parkin knockdown zebrafish. T-tubules are rich in L-type calcium channels, therefore our work might also provide a tentative link between genetically determined early onset Parkinson's disease and recent studies attributing an important role to these L-type calcium channels in late onset sporadic Parkinson's disease.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Laura Flinn</name><affiliations><json:string>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</json:string><json:string>2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</json:string></affiliations></json:item><json:item><name>Heather Mortiboys</name><affiliations><json:string>2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</json:string></affiliations></json:item><json:item><name>Katrin Volkmann</name><affiliations><json:string>3 Helmholtz-Centre Munich, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg-Munich, Germany</json:string></affiliations></json:item><json:item><name>Reinhard W. Köster</name><affiliations><json:string>3 Helmholtz-Centre Munich, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg-Munich, Germany</json:string></affiliations></json:item><json:item><name>Phillip W. Ingham</name><affiliations><json:string>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</json:string></affiliations></json:item><json:item><name>Oliver Bandmann</name><affiliations><json:string>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</json:string><json:string>2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</json:string><json:string>E-mail: o.bandmann@sheffield.ac.uk</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Original Articles</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>mitochondria</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Currently, only symptomatic therapy is available for Parkinson's disease. The zebrafish is a vertebrate animal model ideally suited for high throughput compound screening to identify disease-modifying compounds for Parkinson's disease. We have developed a zebrafish model for Parkin deficiency, the most commonly mutated gene in early onset Parkinson's disease. The zebrafish Parkin protein is 62% identical to its human counterpart with 78% identity in functionally relevant regions. The parkin gene is expressed throughout zebrafish development and ubiquitously in adult zebrafish tissue. Abrogation of Parkin activity leads to a significant decrease in the number of ascending dopaminergic neurons in the posterior tuberculum (homologous to the substantia nigra in humans), an effect enhanced by exposure to MPP+. Both light microscopic analysis and staining with the pan-neuronal marker HuC confirmed that this loss of dopaminergic neurons is not due to general impairment of brain development. Neither serotonergic nor motor neurons were affected, further emphasizing that the effect of parkin knockdown appears to be specific for dopaminergic neurons. Notably, parkin knockdown zebrafish embryos also develop specific reduction in the activity of the mitochondrial respiratory chain complex I, making this the first vertebrate model to share both important pathogenic mechanisms (i.e. complex I deficiency) and the pathological hallmark (i.e. dopaminergic cell loss) with human parkin-mutant patients. The zebrafish model is thus ideally suited for future drug screens and other studies investigating the functional mechanisms underlying neuronal cell death in early onset Parkinson's Disease. Additional electron microscopy studies revealed electron dense material in the t-tubules within the muscle tissue of parkin knockdown zebrafish. T-tubules are rich in L-type calcium channels, therefore our work might also provide a tentative link between genetically determined early onset Parkinson's disease and recent studies attributing an important role to these L-type calcium channels in late onset sporadic Parkinson's disease.</abstract><qualityIndicators><score>8.5</score><pdfVersion>1.4</pdfVersion><pdfPageSize>612.68 x 790.866 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>3</keywordCount><abstractCharCount>2135</abstractCharCount><pdfWordCount>6739</pdfWordCount><pdfCharCount>42826</pdfCharCount><pdfPageCount>11</pdfPageCount><abstractWordCount>298</abstractWordCount></qualityIndicators><title>Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio)</title><genre><json:string>research-article</json:string></genre><host><volume>132</volume><pages><last>1623</last><first>1613</first></pages><issn><json:string>0006-8950</json:string></issn><issue>6</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2156</json:string></eissn><title>Brain</title></host><categories><wos><json:string>CLINICAL NEUROLOGY</json:string><json:string>NEUROSCIENCES</json:string></wos></categories><publicationDate>2009</publicationDate><copyrightDate>2009</copyrightDate><doi><json:string>10.1093/brain/awp108</json:string></doi><id>403604A6D24E1E920E1E90A5F8179825BBADC1ED</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/403604A6D24E1E920E1E90A5F8179825BBADC1ED/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/403604A6D24E1E920E1E90A5F8179825BBADC1ED/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/403604A6D24E1E920E1E90A5F8179825BBADC1ED/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio)</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>OUP</p></availability><date>2009-05-12</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio)</title><author><persName><forename type="first">Laura</forename><surname>Flinn</surname></persName><affiliation>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</affiliation><affiliation>2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</affiliation></author><author><persName><forename type="first">Heather</forename><surname>Mortiboys</surname></persName><affiliation>2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</affiliation></author><author><persName><forename type="first">Katrin</forename><surname>Volkmann</surname></persName><affiliation>3 Helmholtz-Centre Munich, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg-Munich, Germany</affiliation></author><author><persName><forename type="first">Reinhard W.</forename><surname>Köster</surname></persName><affiliation>3 Helmholtz-Centre Munich, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg-Munich, Germany</affiliation></author><author><persName><forename type="first">Phillip W.</forename><surname>Ingham</surname></persName><affiliation>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</affiliation></author><author corresp="yes"><persName><forename type="first">Oliver</forename><surname>Bandmann</surname></persName><email>o.bandmann@sheffield.ac.uk</email><affiliation>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</affiliation><affiliation>2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</affiliation></author></analytic><monogr><title level="j">Brain</title><idno type="pISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2009-06"></date><biblScope unit="volume">132</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="1613">1613</biblScope><biblScope unit="page" to="1623">1623</biblScope></imprint></monogr><idno type="istex">403604A6D24E1E920E1E90A5F8179825BBADC1ED</idno><idno type="DOI">10.1093/brain/awp108</idno><idno type="ArticleID">awp108</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2009-05-12</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Currently, only symptomatic therapy is available for Parkinson's disease. The zebrafish is a vertebrate animal model ideally suited for high throughput compound screening to identify disease-modifying compounds for Parkinson's disease. We have developed a zebrafish model for Parkin deficiency, the most commonly mutated gene in early onset Parkinson's disease. The zebrafish Parkin protein is 62% identical to its human counterpart with 78% identity in functionally relevant regions. The parkin gene is expressed throughout zebrafish development and ubiquitously in adult zebrafish tissue. Abrogation of Parkin activity leads to a significant decrease in the number of ascending dopaminergic neurons in the posterior tuberculum (homologous to the substantia nigra in humans), an effect enhanced by exposure to MPP+. Both light microscopic analysis and staining with the pan-neuronal marker HuC confirmed that this loss of dopaminergic neurons is not due to general impairment of brain development. Neither serotonergic nor motor neurons were affected, further emphasizing that the effect of parkin knockdown appears to be specific for dopaminergic neurons. Notably, parkin knockdown zebrafish embryos also develop specific reduction in the activity of the mitochondrial respiratory chain complex I, making this the first vertebrate model to share both important pathogenic mechanisms (i.e. complex I deficiency) and the pathological hallmark (i.e. dopaminergic cell loss) with human parkin-mutant patients. The zebrafish model is thus ideally suited for future drug screens and other studies investigating the functional mechanisms underlying neuronal cell death in early onset Parkinson's Disease. Additional electron microscopy studies revealed electron dense material in the t-tubules within the muscle tissue of parkin knockdown zebrafish. T-tubules are rich in L-type calcium channels, therefore our work might also provide a tentative link between genetically determined early onset Parkinson's disease and recent studies attributing an important role to these L-type calcium channels in late onset sporadic Parkinson's disease.</p></abstract><textClass><keywords scheme="keyword"><list><item><term>Original Articles</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>Parkinson's disease</term></item><item><term>mitochondria</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2009-05-12">Created</change><change when="2009-06">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/403604A6D24E1E920E1E90A5F8179825BBADC1ED/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="hwp">brain</journal-id><journal-id journal-id-type="publisher-id">brainj</journal-id><journal-title>Brain</journal-title><issn pub-type="ppub">0006-8950</issn><issn pub-type="epub">1460-2156</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/brain/awp108</article-id><article-id pub-id-type="publisher-id">awp108</article-id><article-categories><subj-group><subject>Original Articles</subject></subj-group></article-categories><title-group><article-title>Complex I deficiency and dopaminergic neuronal cell loss in <italic>parkin</italic>-deficient zebrafish (<italic>Danio rerio</italic>)</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Flinn</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref><xref ref-type="aff" rid="AFF2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mortiboys</surname><given-names>Heather</given-names></name><xref ref-type="aff" rid="AFF2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Volkmann</surname><given-names>Katrin</given-names></name><xref ref-type="aff" rid="AFF3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Köster</surname><given-names>Reinhard W.</given-names></name><xref ref-type="aff" rid="AFF3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ingham</surname><given-names>Phillip W.</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Bandmann</surname><given-names>Oliver</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref><xref ref-type="aff" rid="AFF2"><sup>2</sup></xref></contrib></contrib-group><aff id="AFF1">1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</aff><aff id="AFF2">2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</aff><aff id="AFF3">3 Helmholtz-Centre Munich, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg-Munich, Germany</aff><author-notes><corresp>Correspondence to: O. Bandmann, Academic Neurology Unit, Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK E-mail: <email>o.bandmann@sheffield.ac.uk</email></corresp></author-notes><pub-date pub-type="ppub"><month>6</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>12</day><month>5</month><year>2009</year></pub-date><volume>132</volume><issue>6</issue><fpage>1613</fpage><lpage>1623</lpage><history><date date-type="received"><day>9</day><month>12</month><year>2008</year></date><date date-type="rev-recd"><day>5</day><month>3</month><year>2009</year></date><date date-type="accepted"><day>19</day><month>3</month><year>2009</year></date></history><permissions><copyright-statement>© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2009</copyright-year></permissions><abstract><p>Currently, only symptomatic therapy is available for Parkinson's disease. The zebrafish is a vertebrate animal model ideally suited for high throughput compound screening to identify disease-modifying compounds for Parkinson's disease. We have developed a zebrafish model for Parkin deficiency, the most commonly mutated gene in early onset Parkinson's disease. The zebrafish Parkin protein is 62% identical to its human counterpart with 78% identity in functionally relevant regions. The <italic>parkin</italic> gene is expressed throughout zebrafish development and ubiquitously in adult zebrafish tissue. Abrogation of Parkin activity leads to a significant decrease in the number of ascending dopaminergic neurons in the posterior tuberculum (homologous to the substantia nigra in humans), an effect enhanced by exposure to MPP+. Both light microscopic analysis and staining with the pan-neuronal marker HuC confirmed that this loss of dopaminergic neurons is not due to general impairment of brain development. Neither serotonergic nor motor neurons were affected, further emphasizing that the effect of <italic>parkin</italic> knockdown appears to be specific for dopaminergic neurons. Notably, <italic>parkin</italic> knockdown zebrafish embryos also develop specific reduction in the activity of the mitochondrial respiratory chain complex I, making this the first vertebrate model to share both important pathogenic mechanisms (i.e. complex I deficiency) and the pathological hallmark (i.e. dopaminergic cell loss) with human <italic>parkin</italic>-mutant patients. The zebrafish model is thus ideally suited for future drug screens and other studies investigating the functional mechanisms underlying neuronal cell death in early onset Parkinson's Disease. Additional electron microscopy studies revealed electron dense material in the t-tubules within the muscle tissue of <italic>parkin</italic> knockdown zebrafish. T-tubules are rich in L-type calcium channels, therefore our work might also provide a tentative link between genetically determined early onset Parkinson's disease and recent studies attributing an important role to these L-type calcium channels in late onset sporadic Parkinson's disease.</p></abstract><kwd-group><kwd>Parkinson's disease</kwd><kwd>mitochondria</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio)</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio)</title></titleInfo><name type="personal"><namePart type="given">Laura</namePart><namePart type="family">Flinn</namePart><affiliation>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</affiliation><affiliation>2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Heather</namePart><namePart type="family">Mortiboys</namePart><affiliation>2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Katrin</namePart><namePart type="family">Volkmann</namePart><affiliation>3 Helmholtz-Centre Munich, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg-Munich, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Reinhard W.</namePart><namePart type="family">Köster</namePart><affiliation>3 Helmholtz-Centre Munich, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764 Neuherberg-Munich, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Phillip W.</namePart><namePart type="family">Ingham</namePart><affiliation>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Oliver</namePart><namePart type="family">Bandmann</namePart><affiliation>1 MRC Centre for Biomedical and Developmental Genetics, University of Sheffield, Sheffield, UK</affiliation><affiliation>2 Academic Neurology Unit, Medical School, University of Sheffield, Sheffield, UK</affiliation><affiliation>E-mail: o.bandmann@sheffield.ac.uk</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><subject><topic>Original Articles</topic></subject><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2009-06</dateIssued><dateCreated encoding="w3cdtf">2009-05-12</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>Currently, only symptomatic therapy is available for Parkinson's disease. The zebrafish is a vertebrate animal model ideally suited for high throughput compound screening to identify disease-modifying compounds for Parkinson's disease. We have developed a zebrafish model for Parkin deficiency, the most commonly mutated gene in early onset Parkinson's disease. The zebrafish Parkin protein is 62% identical to its human counterpart with 78% identity in functionally relevant regions. The parkin gene is expressed throughout zebrafish development and ubiquitously in adult zebrafish tissue. Abrogation of Parkin activity leads to a significant decrease in the number of ascending dopaminergic neurons in the posterior tuberculum (homologous to the substantia nigra in humans), an effect enhanced by exposure to MPP+. Both light microscopic analysis and staining with the pan-neuronal marker HuC confirmed that this loss of dopaminergic neurons is not due to general impairment of brain development. Neither serotonergic nor motor neurons were affected, further emphasizing that the effect of parkin knockdown appears to be specific for dopaminergic neurons. Notably, parkin knockdown zebrafish embryos also develop specific reduction in the activity of the mitochondrial respiratory chain complex I, making this the first vertebrate model to share both important pathogenic mechanisms (i.e. complex I deficiency) and the pathological hallmark (i.e. dopaminergic cell loss) with human parkin-mutant patients. The zebrafish model is thus ideally suited for future drug screens and other studies investigating the functional mechanisms underlying neuronal cell death in early onset Parkinson's Disease. Additional electron microscopy studies revealed electron dense material in the t-tubules within the muscle tissue of parkin knockdown zebrafish. T-tubules are rich in L-type calcium channels, therefore our work might also provide a tentative link between genetically determined early onset Parkinson's disease and recent studies attributing an important role to these L-type calcium channels in late onset sporadic Parkinson's disease.</abstract><subject><genre>Keywords</genre><topic>Parkinson's disease</topic><topic>mitochondria</topic></subject><relatedItem type="host"><titleInfo><title>Brain</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0006-8950</identifier><identifier type="eISSN">1460-2156</identifier><identifier type="PublisherID">brainj</identifier><identifier type="PublisherID-hwp">brain</identifier><part><date>2009</date><detail type="volume"><caption>vol.</caption><number>132</number></detail><detail type="issue"><caption>no.</caption><number>6</number></detail><extent unit="pages"><start>1613</start><end>1623</end></extent></part></relatedItem><identifier type="istex">403604A6D24E1E920E1E90A5F8179825BBADC1ED</identifier><identifier type="DOI">10.1093/brain/awp108</identifier><identifier type="ArticleID">awp108</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Author (2009). 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