Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human -synuclein in transgenic mouse brain
Identifieur interne : 000560 ( Main/Corpus ); précédent : 000559; suivant : 000561Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human -synuclein in transgenic mouse brain
Auteurs : Kenneth D. Cronin ; Dongliang Ge ; Paul Manninger ; Colton Linnertz ; Anna Rossoshek ; Bonnie M. Orrison ; David J. Bernard ; Omar M. A. El-Agnaf ; Michael G. Schlossmacher ; Robert L. Nussbaum ; Ornit Chiba-FalekSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2009-09-01.
Abstract
-Synuclein (SNCA) gene has been implicated in the development of rare forms of familial Parkinson disease (PD). Recently, it was shown that an increase in SNCA copy numbers leads to elevated levels of wild-type SNCA-mRNA and protein and is sufficient to cause early-onset, familial PD. A critical question concerning the molecular pathogenesis of PD is what contributory role, if any, is played by the SNCA gene in sporadic PD. The expansion of SNCA-Rep1, an upstream, polymorphic microsatellite of the SNCA gene, is associated with elevated risk for sporadic PD. However, whether SNCA-Rep1 is the causal variant and the underlying mechanism with which its effect is mediated by remained elusive. We report here the effects of three distinct SNCA-Rep1 variants in the brains of 72 mice transgenic for the entire human SNCA locus. Human SNCA-mRNA and protein levels were increased 1.7- and 1.25-fold, respectively, in homozygotes for the expanded, PD risk-conferring allele compared with homozygotes for the shorter, protective allele. When adjusting for the total SNCA-protein concentration (endogenous mouse and transgenic human) expressed in each brain, the expanded risk allele contributed 2.6-fold more to the SNCA steady-state than the shorter allele. Furthermore, targeted deletion of Rep1 resulted in the lowest human SNCA-mRNA and protein concentrations in murine brain. In contrast, the Rep1 effect was not observed in blood lysates from the same mice. These results demonstrate that Rep1 regulates human SNCA expression by enhancing its transcription in the adult nervous system and suggest that homozygosity for the expanded Rep1 allele may mimic locus multiplication, thereby elevating PD risk.
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DOI: 10.1093/hmg/ddp265
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Cronin</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Ge, Dongliang" sort="Ge, Dongliang" uniqKey="Ge D" first="Dongliang" last="Ge">Dongliang Ge</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Manninger, Paul" sort="Manninger, Paul" uniqKey="Manninger P" first="Paul" last="Manninger">Paul Manninger</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Linnertz, Colton" sort="Linnertz, Colton" uniqKey="Linnertz C" first="Colton" last="Linnertz">Colton Linnertz</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Rossoshek, Anna" sort="Rossoshek, Anna" uniqKey="Rossoshek A" first="Anna" last="Rossoshek">Anna Rossoshek</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Orrison, Bonnie M" sort="Orrison, Bonnie M" uniqKey="Orrison B" first="Bonnie M." last="Orrison">Bonnie M. 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Cronin</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Ge, Dongliang" sort="Ge, Dongliang" uniqKey="Ge D" first="Dongliang" last="Ge">Dongliang Ge</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Manninger, Paul" sort="Manninger, Paul" uniqKey="Manninger P" first="Paul" last="Manninger">Paul Manninger</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Linnertz, Colton" sort="Linnertz, Colton" uniqKey="Linnertz C" first="Colton" last="Linnertz">Colton Linnertz</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Rossoshek, Anna" sort="Rossoshek, Anna" uniqKey="Rossoshek A" first="Anna" last="Rossoshek">Anna Rossoshek</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Orrison, Bonnie M" sort="Orrison, Bonnie M" uniqKey="Orrison B" first="Bonnie M." last="Orrison">Bonnie M. Orrison</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Bernard, David J" sort="Bernard, David J" uniqKey="Bernard D" first="David J." last="Bernard">David J. Bernard</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="El Agnaf, Omar M A" sort="El Agnaf, Omar M A" uniqKey="El Agnaf O" first="Omar M. A." last="El-Agnaf">Omar M. A. El-Agnaf</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Schlossmacher, Michael G" sort="Schlossmacher, Michael G" uniqKey="Schlossmacher M" first="Michael G." last="Schlossmacher">Michael G. Schlossmacher</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Nussbaum, Robert L" sort="Nussbaum, Robert L" uniqKey="Nussbaum R" first="Robert L." last="Nussbaum">Robert L. Nussbaum</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Chiba Falek, Ornit" sort="Chiba Falek, Ornit" uniqKey="Chiba Falek O" first="Ornit" last="Chiba-Falek">Ornit Chiba-Falek</name><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: o.chibafalek@duke.edu</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="2009-09-01">2009-09-01</date><biblScope unit="volume">18</biblScope><biblScope unit="issue">17</biblScope><biblScope unit="page" from="3274">3274</biblScope><biblScope unit="page" to="3285">3285</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">01266ADBFF094A2FC9962CC9996BC24FC377A88D</idno><idno type="DOI">10.1093/hmg/ddp265</idno><idno type="ArticleID">ddp265</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">-Synuclein (SNCA) gene has been implicated in the development of rare forms of familial Parkinson disease (PD). Recently, it was shown that an increase in SNCA copy numbers leads to elevated levels of wild-type SNCA-mRNA and protein and is sufficient to cause early-onset, familial PD. A critical question concerning the molecular pathogenesis of PD is what contributory role, if any, is played by the SNCA gene in sporadic PD. The expansion of SNCA-Rep1, an upstream, polymorphic microsatellite of the SNCA gene, is associated with elevated risk for sporadic PD. However, whether SNCA-Rep1 is the causal variant and the underlying mechanism with which its effect is mediated by remained elusive. We report here the effects of three distinct SNCA-Rep1 variants in the brains of 72 mice transgenic for the entire human SNCA locus. Human SNCA-mRNA and protein levels were increased 1.7- and 1.25-fold, respectively, in homozygotes for the expanded, PD risk-conferring allele compared with homozygotes for the shorter, protective allele. When adjusting for the total SNCA-protein concentration (endogenous mouse and transgenic human) expressed in each brain, the expanded risk allele contributed 2.6-fold more to the SNCA steady-state than the shorter allele. Furthermore, targeted deletion of Rep1 resulted in the lowest human SNCA-mRNA and protein concentrations in murine brain. In contrast, the Rep1 effect was not observed in blood lysates from the same mice. These results demonstrate that Rep1 regulates human SNCA expression by enhancing its transcription in the adult nervous system and suggest that homozygosity for the expanded Rep1 allele may mimic locus multiplication, thereby elevating PD risk.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Kenneth D. Cronin</name><affiliations><json:string>Center for Human Genome Variation, Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA</json:string></affiliations></json:item><json:item><name>Dongliang Ge</name><affiliations><json:string>Center for Human Genome Variation, Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA</json:string></affiliations></json:item><json:item><name>Paul Manninger</name><affiliations><json:string>Division of Neurosciences, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5</json:string></affiliations></json:item><json:item><name>Colton Linnertz</name><affiliations><json:string>Center for Human Genome Variation, Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA</json:string></affiliations></json:item><json:item><name>Anna Rossoshek</name><affiliations><json:string>Genetic Disease Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, MD 20892-4472, USA</json:string></affiliations></json:item><json:item><name>Bonnie M. Orrison</name><affiliations><json:string>Genetic Disease Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, MD 20892-4472, USA</json:string></affiliations></json:item><json:item><name>David J. Bernard</name><affiliations><json:string>Genetic Disease Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, MD 20892-4472, USA</json:string></affiliations></json:item><json:item><name>Omar M.A. El-Agnaf</name><affiliations><json:string>Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE</json:string></affiliations></json:item><json:item><name>Michael G. Schlossmacher</name><affiliations><json:string>Division of Neurosciences, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5</json:string></affiliations></json:item><json:item><name>Robert L. Nussbaum</name><affiliations><json:string>Division of Medical Genetics, Institute for Human Genetics, University of California, San Francisco, CA 94143, USA</json:string></affiliations></json:item><json:item><name>Ornit Chiba-Falek</name><affiliations><json:string>Center for Human Genome Variation, Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA</json:string><json:string>Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC 27708, USA</json:string><json:string>E-mail: o.chibafalek@duke.edu</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>-Synuclein (SNCA) gene has been implicated in the development of rare forms of familial Parkinson disease (PD). Recently, it was shown that an increase in SNCA copy numbers leads to elevated levels of wild-type SNCA-mRNA and protein and is sufficient to cause early-onset, familial PD. A critical question concerning the molecular pathogenesis of PD is what contributory role, if any, is played by the SNCA gene in sporadic PD. The expansion of SNCA-Rep1, an upstream, polymorphic microsatellite of the SNCA gene, is associated with elevated risk for sporadic PD. However, whether SNCA-Rep1 is the causal variant and the underlying mechanism with which its effect is mediated by remained elusive. We report here the effects of three distinct SNCA-Rep1 variants in the brains of 72 mice transgenic for the entire human SNCA locus. Human SNCA-mRNA and protein levels were increased 1.7- and 1.25-fold, respectively, in homozygotes for the expanded, PD risk-conferring allele compared with homozygotes for the shorter, protective allele. When adjusting for the total SNCA-protein concentration (endogenous mouse and transgenic human) expressed in each brain, the expanded risk allele contributed 2.6-fold more to the SNCA steady-state than the shorter allele. Furthermore, targeted deletion of Rep1 resulted in the lowest human SNCA-mRNA and protein concentrations in murine brain. In contrast, the Rep1 effect was not observed in blood lysates from the same mice. These results demonstrate that Rep1 regulates human SNCA expression by enhancing its transcription in the adult nervous system and suggest that homozygosity for the expanded Rep1 allele may mimic locus multiplication, thereby elevating PD risk.</abstract><qualityIndicators><score>9</score><pdfVersion>1.5</pdfVersion><pdfPageSize>612 x 797.953 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>1</keywordCount><abstractCharCount>1706</abstractCharCount><pdfWordCount>9313</pdfWordCount><pdfCharCount>57836</pdfCharCount><pdfPageCount>12</pdfPageCount><abstractWordCount>257</abstractWordCount></qualityIndicators><title>Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human -synuclein in transgenic mouse 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type="first">Anna</forename><surname>Rossoshek</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Bonnie M.</forename><surname>Orrison</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">David J.</forename><surname>Bernard</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Omar M.A.</forename><surname>El-Agnaf</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Michael G.</forename><surname>Schlossmacher</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Robert L.</forename><surname>Nussbaum</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Ornit</forename><surname>Chiba-Falek</surname></persName><email>o.chibafalek@duke.edu</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="2009-09-01"></date><biblScope unit="volume">18</biblScope><biblScope unit="issue">17</biblScope><biblScope unit="page" from="3274">3274</biblScope><biblScope unit="page" to="3285">3285</biblScope></imprint></monogr><idno type="istex">01266ADBFF094A2FC9962CC9996BC24FC377A88D</idno><idno type="DOI">10.1093/hmg/ddp265</idno><idno type="ArticleID">ddp265</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2009-06-04</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>-Synuclein (SNCA) gene has been implicated in the development of rare forms of familial Parkinson disease (PD). Recently, it was shown that an increase in SNCA copy numbers leads to elevated levels of wild-type SNCA-mRNA and protein and is sufficient to cause early-onset, familial PD. A critical question concerning the molecular pathogenesis of PD is what contributory role, if any, is played by the SNCA gene in sporadic PD. The expansion of SNCA-Rep1, an upstream, polymorphic microsatellite of the SNCA gene, is associated with elevated risk for sporadic PD. However, whether SNCA-Rep1 is the causal variant and the underlying mechanism with which its effect is mediated by remained elusive. We report here the effects of three distinct SNCA-Rep1 variants in the brains of 72 mice transgenic for the entire human SNCA locus. Human SNCA-mRNA and protein levels were increased 1.7- and 1.25-fold, respectively, in homozygotes for the expanded, PD risk-conferring allele compared with homozygotes for the shorter, protective allele. When adjusting for the total SNCA-protein concentration (endogenous mouse and transgenic human) expressed in each brain, the expanded risk allele contributed 2.6-fold more to the SNCA steady-state than the shorter allele. Furthermore, targeted deletion of Rep1 resulted in the lowest human SNCA-mRNA and protein concentrations in murine brain. In contrast, the Rep1 effect was not observed in blood lysates from the same mice. These results demonstrate that Rep1 regulates human SNCA expression by enhancing its transcription in the adult nervous system and suggest that homozygosity for the expanded Rep1 allele may mimic locus multiplication, thereby elevating PD risk.</p></abstract></profileDesc><revisionDesc><change when="2009-06-04">Created</change><change when="2009-09-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-14">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/01266ADBFF094A2FC9962CC9996BC24FC377A88D/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/ddp265</article-id><article-id pub-id-type="publisher-id">ddp265</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Expansion of the Parkinson disease-associated <italic>SNCA-</italic>Rep1 allele upregulates human α-synuclein in transgenic mouse brain</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Cronin</surname><given-names>Kenneth D.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ge</surname><given-names>Dongliang</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Manninger</surname><given-names>Paul</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Linnertz</surname><given-names>Colton</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Rossoshek</surname><given-names>Anna</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Orrison</surname><given-names>Bonnie M.</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Bernard</surname><given-names>David J.</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>El-Agnaf</surname><given-names>Omar M.A.</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Schlossmacher</surname><given-names>Michael G.</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Nussbaum</surname><given-names>Robert L.</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Chiba-Falek</surname><given-names>Ornit</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af6">6</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><institution>Center for Human Genome Variation, Institute for Genome Sciences and Policy, Duke University</institution>, <addr-line>Durham, NC 27708</addr-line>, <country>USA</country></aff><aff id="af2"><label>2</label><addr-line>Division of Neurosciences, Ottawa Health Research Institute</addr-line>, <institution>University of Ottawa</institution>, <addr-line>Ottawa, Ontario</addr-line>, <country>Canada</country> <addr-line>K1H 8M5</addr-line></aff><aff id="af3"><label>3</label><addr-line>Genetic Disease Research Branch</addr-line>, <institution>National Human Genome Research Institute, National Institute of Health</institution>, <addr-line>Bethesda, MD 20892-4472</addr-line>, <country>USA</country></aff><aff id="af4"><label>4</label><addr-line>Department of Biochemistry, Faculty of Medicine and Health Sciences</addr-line>, <institution>United Arab Emirates University</institution>, <addr-line>Al Ain</addr-line>, <country>UAE</country></aff><aff id="af5"><label>5</label><addr-line>Division of Medical Genetics</addr-line>, <institution>Institute for Human Genetics, University of California</institution>, <addr-line>San Francisco, CA 94143</addr-line>, <country>USA</country></aff><aff id="af6"><label>6</label><addr-line>Division of Neurology, Department of Medicine</addr-line>, <institution>Duke University Medical Center</institution>, <addr-line>Durham, NC 27708</addr-line>, <country>USA</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: <institution>Center for Human Genome Variation, Duke Institute for Genome Sciences and Policy</institution>, <addr-line>DUMC Box 91009, Duke University, Durham, NC 27708</addr-line>, <country>USA</country>. Tel: <phone>+1 9196818001</phone>; Fax: <fax>+1 9196136448</fax>; Email: <email>o.chibafalek@duke.edu</email></corresp></author-notes><pub-date pub-type="ppub"><day>1</day><month>9</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>4</day><month>6</month><year>2009</year></pub-date><volume>18</volume><issue>17</issue><fpage>3274</fpage><lpage>3285</lpage><history><date date-type="received"><day>9</day><month>3</month><year>2009</year></date><date date-type="accepted"><day>1</day><month>6</month><year>2009</year></date></history><copyright-statement>© 2009 The Author(s)</copyright-statement><copyright-year>2009</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.0/uk/"><p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></license><abstract><p>α-Synuclein (<italic>SNCA)</italic> gene has been implicated in the development of rare forms of familial Parkinson disease (PD). Recently, it was shown that an increase in <italic>SNCA</italic> copy numbers leads to elevated levels of wild-type <italic>SNCA-</italic>mRNA and protein and is sufficient to cause early-onset, familial PD. A critical question concerning the molecular pathogenesis of PD is what contributory role, if any, is played by the <italic>SNCA</italic> gene in sporadic PD. The expansion of <italic>SNCA</italic>-Rep1, an upstream, polymorphic microsatellite of the <italic>SNCA</italic> gene, is associated with elevated risk for sporadic PD. However, whether <italic>SNCA</italic>-Rep1 is the causal variant and the underlying mechanism with which its effect is mediated by remained elusive. We report here the effects of three distinct <italic>SNCA</italic>-Rep1 variants in the brains of 72 mice transgenic for the entire human <italic>SNCA</italic> locus. Human <italic>SNCA</italic>-mRNA and protein levels were increased 1.7- and 1.25-fold, respectively, in homozygotes for the expanded, PD risk-conferring allele compared with homozygotes for the shorter, protective allele. When adjusting for the total SNCA-protein concentration (endogenous mouse and transgenic human) expressed in each brain, the expanded risk allele contributed 2.6-fold more to the SNCA steady-state than the shorter allele. Furthermore, targeted deletion of Rep1 resulted in the lowest human <italic>SNCA-</italic>mRNA and protein concentrations in murine brain. In contrast, the Rep1 effect was not observed in blood lysates from the same mice. These results demonstrate that Rep1 regulates human <italic>SNCA</italic> expression by enhancing its transcription in the adult nervous system and suggest that homozygosity for the expanded Rep1 allele may mimic locus multiplication, thereby elevating PD risk.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human -synuclein in transgenic mouse brain</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human -synuclein in transgenic mouse brain</title></titleInfo><name type="personal"><namePart type="given">Kenneth D.</namePart><namePart type="family">Cronin</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dongliang</namePart><namePart type="family">Ge</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paul</namePart><namePart type="family">Manninger</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Colton</namePart><namePart type="family">Linnertz</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anna</namePart><namePart type="family">Rossoshek</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Bonnie M.</namePart><namePart type="family">Orrison</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David J.</namePart><namePart type="family">Bernard</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Omar M.A.</namePart><namePart type="family">El-Agnaf</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael G.</namePart><namePart type="family">Schlossmacher</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Robert L.</namePart><namePart type="family">Nussbaum</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ornit</namePart><namePart type="family">Chiba-Falek</namePart><affiliation></affiliation><affiliation></affiliation><affiliation>E-mail: o.chibafalek@duke.edu</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">2009-09-01</dateIssued><dateCreated encoding="w3cdtf">2009-06-04</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>-Synuclein (SNCA) gene has been implicated in the development of rare forms of familial Parkinson disease (PD). Recently, it was shown that an increase in SNCA copy numbers leads to elevated levels of wild-type SNCA-mRNA and protein and is sufficient to cause early-onset, familial PD. A critical question concerning the molecular pathogenesis of PD is what contributory role, if any, is played by the SNCA gene in sporadic PD. The expansion of SNCA-Rep1, an upstream, polymorphic microsatellite of the SNCA gene, is associated with elevated risk for sporadic PD. However, whether SNCA-Rep1 is the causal variant and the underlying mechanism with which its effect is mediated by remained elusive. We report here the effects of three distinct SNCA-Rep1 variants in the brains of 72 mice transgenic for the entire human SNCA locus. Human SNCA-mRNA and protein levels were increased 1.7- and 1.25-fold, respectively, in homozygotes for the expanded, PD risk-conferring allele compared with homozygotes for the shorter, protective allele. When adjusting for the total SNCA-protein concentration (endogenous mouse and transgenic human) expressed in each brain, the expanded risk allele contributed 2.6-fold more to the SNCA steady-state than the shorter allele. Furthermore, targeted deletion of Rep1 resulted in the lowest human SNCA-mRNA and protein concentrations in murine brain. In contrast, the Rep1 effect was not observed in blood lysates from the same mice. These results demonstrate that Rep1 regulates human SNCA expression by enhancing its transcription in the adult nervous system and suggest that homozygosity for the expanded Rep1 allele may mimic locus multiplication, thereby elevating PD risk.</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>2009</date><detail type="volume"><caption>vol.</caption><number>18</number></detail><detail type="issue"><caption>no.</caption><number>17</number></detail><extent unit="pages"><start>3274</start><end>3285</end></extent></part></relatedItem><identifier type="istex">01266ADBFF094A2FC9962CC9996BC24FC377A88D</identifier><identifier type="DOI">10.1093/hmg/ddp265</identifier><identifier type="ArticleID">ddp265</identifier><accessCondition type="use and reproduction" contentType="copyright">2009 The Author(s)</accessCondition><recordInfo><recordContentSource>OUP</recordContentSource></recordInfo></mods></metadata><covers><json:item><original>true</original><mimetype>image/tiff</mimetype><extension>tiff</extension><uri>https://api.istex.fr/document/01266ADBFF094A2FC9962CC9996BC24FC377A88D/covers/tiff</uri></json:item><json:item><original>true</original><mimetype>text/html</mimetype><extension>html</extension><uri>https://api.istex.fr/document/01266ADBFF094A2FC9962CC9996BC24FC377A88D/covers/html</uri></json:item></covers><annexes><json:item><original>true</original><mimetype>image/jpeg</mimetype><extension>jpeg</extension><uri>https://api.istex.fr/document/01266ADBFF094A2FC9962CC9996BC24FC377A88D/annexes/jpeg</uri></json:item><json:item><original>true</original><mimetype>image/gif</mimetype><extension>gif</extension><uri>https://api.istex.fr/document/01266ADBFF094A2FC9962CC9996BC24FC377A88D/annexes/gif</uri></json:item></annexes><enrichments><istex:catWosTEI uri="https://api.istex.fr/document/01266ADBFF094A2FC9962CC9996BC24FC377A88D/enrichments/catWos"><teiHeader><profileDesc><textClass><classCode scheme="WOS">BIOCHEMISTRY & MOLECULAR BIOLOGY</classCode><classCode scheme="WOS">GENETICS & HEREDITY</classCode></textClass></profileDesc></teiHeader></istex:catWosTEI></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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