Synphilin-1 attenuates neuronal degeneration in the A53T -synuclein transgenic mouse model
Identifieur interne : 001F61 ( Main/Corpus ); précédent : 001F60; suivant : 001F62Synphilin-1 attenuates neuronal degeneration in the A53T -synuclein transgenic mouse model
Auteurs : Wanli W. Smith ; Zhaohui Liu ; Yideng Liang ; Naoki Masuda ; Debbie A. Swing ; Nancy A. Jenkins ; Neal G. Copeland ; Juan C. Troncoso ; Mikhail Pletnikov ; Ted M. Dawson ; Lee J. Martin ; Timothy H. Moran ; Michael K. Lee ; David R. Borchelt ; Christopher A. RossSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-06-01.
Abstract
Genetic alterations in -synuclein cause autosomal dominant familial Parkinsonism and may contribute to sporadic Parkinson's disease (PD). Synphilin-1 is an -synuclein-interacting protein, with implications in PD pathogenesis related to protein aggregation. Currently, the in vivo role of synphilin-1 in -synuclein-linked pathogenesis is not fully understood. Using the mouse prion protein promoter, we generated synphilin-1 transgenic mice, which did not display PD-like phenotypes. However, synphilin-1/A53T -synuclein double-transgenic mice survived longer than A53T -synuclein single-transgenic mice. There were attenuated A53T -synuclein-induced motor abnormalities and decreased astroglial reaction and neuronal degeneration in brains in double-transgenic mice. Overexpression of synphilin-1 decreased caspase-3 activation, increased beclin-1 and LC3 II expression and promoted formation of aggresome-like structures, suggesting that synphilin-1 alters multiple cellular pathways to protect against neuronal degeneration. These studies demonstrate that synphilin-1 can diminish the severity of -synucleinopathy and play a neuroprotective role against A53T -synuclein toxicity in vivo.
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DOI: 10.1093/hmg/ddq086
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Ross</name><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: wsmith@rx.umaryland.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="2010-06-01">2010-06-01</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="2087">2087</biblScope><biblScope unit="page" to="2098">2098</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">09A00FB694C02AD73462BB3EC858266D3FAB70D7</idno><idno type="DOI">10.1093/hmg/ddq086</idno><idno type="ArticleID">ddq086</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">Genetic alterations in -synuclein cause autosomal dominant familial Parkinsonism and may contribute to sporadic Parkinson's disease (PD). Synphilin-1 is an -synuclein-interacting protein, with implications in PD pathogenesis related to protein aggregation. Currently, the in vivo role of synphilin-1 in -synuclein-linked pathogenesis is not fully understood. Using the mouse prion protein promoter, we generated synphilin-1 transgenic mice, which did not display PD-like phenotypes. However, synphilin-1/A53T -synuclein double-transgenic mice survived longer than A53T -synuclein single-transgenic mice. There were attenuated A53T -synuclein-induced motor abnormalities and decreased astroglial reaction and neuronal degeneration in brains in double-transgenic mice. Overexpression of synphilin-1 decreased caspase-3 activation, increased beclin-1 and LC3 II expression and promoted formation of aggresome-like structures, suggesting that synphilin-1 alters multiple cellular pathways to protect against neuronal degeneration. These studies demonstrate that synphilin-1 can diminish the severity of -synucleinopathy and play a neuroprotective role against A53T -synuclein toxicity in vivo.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Wanli W. Smith</name><affiliations><json:string>Division of Neurobiology, Department of Psychiatry,</json:string><json:string>Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA,</json:string><json:string>E-mail: wsmith@rx.umaryland.edu</json:string></affiliations></json:item><json:item><name>Zhaohui Liu</name><affiliations><json:string>Division of Neurobiology, Department of Psychiatry,</json:string><json:string>Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA,</json:string></affiliations></json:item><json:item><name>Yideng Liang</name><affiliations><json:string>Division of Neurobiology, Department of Psychiatry,</json:string></affiliations></json:item><json:item><name>Naoki Masuda</name><affiliations><json:string>Division of Neurobiology, Department of Psychiatry,</json:string></affiliations></json:item><json:item><name>Debbie A. Swing</name><affiliations><json:string>Mouse Cancer Genetics Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA and</json:string></affiliations></json:item><json:item><name>Nancy A. Jenkins</name><affiliations><json:string>Mouse Cancer Genetics Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA and</json:string></affiliations></json:item><json:item><name>Neal G. Copeland</name><affiliations><json:string>Mouse Cancer Genetics Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA and</json:string></affiliations></json:item><json:item><name>Juan C. Troncoso</name><affiliations><json:string>Department of Pathology,</json:string></affiliations></json:item><json:item><name>Mikhail Pletnikov</name><affiliations><json:string>Division of Neurobiology, Department of Psychiatry,</json:string><json:string>Department of Neuroscience,</json:string><json:string>Cellular and Molecular Medicine Program and</json:string></affiliations></json:item><json:item><name>Ted M. Dawson</name><affiliations><json:string>Department of Neuroscience,</json:string><json:string>Department of Neurology,</json:string><json:string>Neuroregeneration and Stem Cell Programs, Institute For Cell Engineering,</json:string></affiliations></json:item><json:item><name>Lee J. Martin</name><affiliations><json:string>Department of Pathology,</json:string></affiliations></json:item><json:item><name>Timothy H. Moran</name><affiliations><json:string>Division of Behavioral Neuroscience, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA,</json:string></affiliations></json:item><json:item><name>Michael K. Lee</name><affiliations><json:string>Department of Neuroscience, University of Minnesota, USA</json:string></affiliations></json:item><json:item><name>David R. Borchelt</name><affiliations><json:string>Department of Pathology,</json:string></affiliations></json:item><json:item><name>Christopher A. Ross</name><affiliations><json:string>Division of Neurobiology, Department of Psychiatry,</json:string><json:string>Department of Neuroscience,</json:string><json:string>Department of Neurology,</json:string><json:string>Department of Pharmacology,</json:string><json:string>Cellular and Molecular Medicine Program and</json:string><json:string>E-mail: wsmith@rx.umaryland.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>Genetic alterations in -synuclein cause autosomal dominant familial Parkinsonism and may contribute to sporadic Parkinson's disease (PD). Synphilin-1 is an -synuclein-interacting protein, with implications in PD pathogenesis related to protein aggregation. Currently, the in vivo role of synphilin-1 in -synuclein-linked pathogenesis is not fully understood. Using the mouse prion protein promoter, we generated synphilin-1 transgenic mice, which did not display PD-like phenotypes. However, synphilin-1/A53T -synuclein double-transgenic mice survived longer than A53T -synuclein single-transgenic mice. There were attenuated A53T -synuclein-induced motor abnormalities and decreased astroglial reaction and neuronal degeneration in brains in double-transgenic mice. Overexpression of synphilin-1 decreased caspase-3 activation, increased beclin-1 and LC3 II expression and promoted formation of aggresome-like structures, suggesting that synphilin-1 alters multiple cellular pathways to protect against neuronal degeneration. These studies demonstrate that synphilin-1 can diminish the severity of -synucleinopathy and play a neuroprotective role against A53T -synuclein toxicity in vivo.</abstract><qualityIndicators><score>7.74</score><pdfVersion>1.5</pdfVersion><pdfPageSize>612 x 797.953 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>1</keywordCount><abstractCharCount>1189</abstractCharCount><pdfWordCount>6243</pdfWordCount><pdfCharCount>43094</pdfCharCount><pdfPageCount>12</pdfPageCount><abstractWordCount>145</abstractWordCount></qualityIndicators><title>Synphilin-1 attenuates neuronal degeneration in the A53T -synuclein transgenic mouse model</title><genre><json:string>research-article</json:string></genre><host><volume>19</volume><pages><last>2098</last><first>2087</first></pages><issn><json:string>0964-6906</json:string></issn><issue>11</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2083</json:string></eissn><title>Human Molecular 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type="first">Yideng</forename><surname>Liang</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Naoki</forename><surname>Masuda</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Debbie A.</forename><surname>Swing</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Nancy A.</forename><surname>Jenkins</surname></persName><note type="biography">Present address: Institute of Molecular and Cell Biology, Singapore, 138673.</note><affiliation>Present address: Institute of Molecular and Cell Biology, Singapore, 138673.</affiliation><affiliation></affiliation></author><author><persName><forename type="first">Neal G.</forename><surname>Copeland</surname></persName><note type="biography">Present address: Institute of Molecular and Cell Biology, Singapore, 138673.</note><affiliation>Present address: Institute of Molecular and Cell Biology, Singapore, 138673.</affiliation><affiliation></affiliation></author><author><persName><forename type="first">Juan C.</forename><surname>Troncoso</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Mikhail</forename><surname>Pletnikov</surname></persName><affiliation></affiliation><affiliation></affiliation><affiliation></affiliation></author><author><persName><forename type="first">Ted M.</forename><surname>Dawson</surname></persName><affiliation></affiliation><affiliation></affiliation><affiliation></affiliation></author><author><persName><forename type="first">Lee J.</forename><surname>Martin</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Timothy H.</forename><surname>Moran</surname></persName><affiliation>7, USA,</affiliation></author><author><persName><forename type="first">Michael K.</forename><surname>Lee</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">David R.</forename><surname>Borchelt</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Christopher A.</forename><surname>Ross</surname></persName><email>wsmith@rx.umaryland.edu</email><affiliation></affiliation><affiliation></affiliation><affiliation></affiliation><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="2010-06-01"></date><biblScope unit="volume">19</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="2087">2087</biblScope><biblScope unit="page" to="2098">2098</biblScope></imprint></monogr><idno type="istex">09A00FB694C02AD73462BB3EC858266D3FAB70D7</idno><idno type="DOI">10.1093/hmg/ddq086</idno><idno 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Synphilin-1 is an -synuclein-interacting protein, with implications in PD pathogenesis related to protein aggregation. Currently, the in vivo role of synphilin-1 in -synuclein-linked pathogenesis is not fully understood. Using the mouse prion protein promoter, we generated synphilin-1 transgenic mice, which did not display PD-like phenotypes. However, synphilin-1/A53T -synuclein double-transgenic mice survived longer than A53T -synuclein single-transgenic mice. There were attenuated A53T -synuclein-induced motor abnormalities and decreased astroglial reaction and neuronal degeneration in brains in double-transgenic mice. Overexpression of synphilin-1 decreased caspase-3 activation, increased beclin-1 and LC3 II expression and promoted formation of aggresome-like structures, suggesting that synphilin-1 alters multiple cellular pathways to protect against neuronal degeneration. These studies demonstrate that synphilin-1 can diminish the severity of -synucleinopathy and play a neuroprotective role against A53T -synuclein toxicity in vivo.</p></abstract></profileDesc><revisionDesc><change when="2010-02-25">Created</change><change when="2010-06-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-15">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/09A00FB694C02AD73462BB3EC858266D3FAB70D7/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/ddq086</article-id><article-id pub-id-type="publisher-id">ddq086</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Synphilin-1 attenuates neuronal degeneration in the A53T &agr;-synuclein transgenic mouse model</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Smith</surname><given-names>Wanli W.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af9">9</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Zhaohui</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Liang</surname><given-names>Yideng</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Masuda</surname><given-names>Naoki</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Swing</surname><given-names>Debbie A.</given-names></name><xref ref-type="aff" rid="af10">10</xref></contrib><contrib contrib-type="author"><name><surname>Jenkins</surname><given-names>Nancy A.</given-names></name><xref ref-type="aff" rid="af10">10</xref><xref ref-type="fn" rid="AN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Copeland</surname><given-names>Neal G.</given-names></name><xref ref-type="aff" rid="af10">10</xref><xref ref-type="fn" rid="AN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Troncoso</surname><given-names>Juan C.</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Pletnikov</surname><given-names>Mikhail</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Dawson</surname><given-names>Ted M.</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Martin</surname><given-names>Lee J.</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Moran</surname><given-names>Timothy H.</given-names></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Michael K.</given-names></name><xref ref-type="aff" rid="af11">11</xref></contrib><contrib contrib-type="author"><name><surname>Borchelt</surname><given-names>David R.</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Ross</surname><given-names>Christopher A.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af5">5</xref><xref ref-type="aff" rid="af7">7</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Division of Neurobiology, Department of Psychiatry</addr-line>,</aff><aff id="af2"><label>2</label><addr-line>Department of Neuroscience</addr-line>,</aff><aff id="af3"><label>3</label><addr-line>Department of Neurology</addr-line>,</aff><aff id="af4"><label>4</label><addr-line>Department of Pathology</addr-line>,</aff><aff id="af5"><label>5</label><addr-line>Department of Pharmacology</addr-line>,</aff><aff id="af6"><label>6</label><addr-line>Neuroregeneration and Stem Cell Programs</addr-line>, <institution>Institute For Cell Engineering</institution>,</aff><aff id="af7"><label>7</label><addr-line>Cellular and Molecular Medicine Program</addr-line> and</aff><aff id="af8"><label>8</label><addr-line>Division of Behavioral Neuroscience, Department of Psychiatry</addr-line>, <institution>Johns Hopkins University School of Medicine</institution>, <addr-line>Baltimore, MD 21287</addr-line>, <country>USA</country>,</aff><aff id="af9"><label>9</label><addr-line>Department of Pharmaceutical Sciences</addr-line>, <institution>University of Maryland School of Pharmacy</institution>, <addr-line>20 Penn Street, Baltimore, MD 21201</addr-line>, <country>USA</country>,</aff><aff id="af10"><label>10</label><addr-line>Mouse Cancer Genetics Program</addr-line>, <institution>NCI-Frederick Cancer Research and Development Center</institution>, <addr-line>Frederick, MD 21702</addr-line>, <country>USA</country> and</aff><aff id="af11"><label>11</label><addr-line>Department of Neuroscience</addr-line>, <institution>University of Minnesota</institution>, <country>USA</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: <addr-line>Department of Pharmaceutical Sciences</addr-line>, <institution>University of Maryland School of Pharmacy</institution>, <addr-line>20 Penn Street, Baltimore, MD 21201</addr-line>, <country>USA</country>. Tel: <phone>+1 4107063579</phone>; Fax: <fax>+1 4107065017</fax>; Email: <email>wsmith@rx.umaryland.edu</email> (W.W.S.); <addr-line>Division of Neurobiology, Department of Psychiatry</addr-line>, <institution>Johns Hopkins University School of Medicine</institution>, <addr-line>CMSC 8-120, 600 North Wolfe Street, Baltimore, MD 21287</addr-line>, <country>USA</country>. Tel: <phone>+1 4106140011</phone>; Fax: <fax>+1 4106140013</fax>; Email: <email>caross@jhu.edu</email> (C.A.R.)</corresp><fn id="AN1"><label>†</label><p>Present address: Institute of Molecular and Cell Biology, Singapore, 138673.</p></fn></author-notes><pub-date pub-type="ppub"><day>1</day><month>6</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>25</day><month>2</month><year>2010</year></pub-date><volume>19</volume><issue>11</issue><fpage>2087</fpage><lpage>2098</lpage><history><date date-type="received"><day>23</day><month>9</month><year>2009</year></date><date date-type="accepted"><day>22</day><month>2</month><year>2010</year></date></history><permissions><copyright-statement>© The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2010</copyright-year></permissions><abstract><p>Genetic alterations in &agr;-synuclein cause autosomal dominant familial Parkinsonism and may contribute to sporadic Parkinson's disease (PD). Synphilin-1 is an &agr;-synuclein-interacting protein, with implications in PD pathogenesis related to protein aggregation. Currently, the <italic>in vivo</italic> role of synphilin-1 in &agr;-synuclein-linked pathogenesis is not fully understood. Using the mouse prion protein promoter, we generated synphilin-1 transgenic mice, which did not display PD-like phenotypes. However, synphilin-1/A53T &agr;-synuclein double-transgenic mice survived longer than A53T &agr;-synuclein single-transgenic mice. There were attenuated A53T &agr;-synuclein-induced motor abnormalities and decreased astroglial reaction and neuronal degeneration in brains in double-transgenic mice. Overexpression of synphilin-1 decreased caspase-3 activation, increased beclin-1 and LC3 II expression and promoted formation of aggresome-like structures, suggesting that synphilin-1 alters multiple cellular pathways to protect against neuronal degeneration. These studies demonstrate that synphilin-1 can diminish the severity of &agr;-synucleinopathy and play a neuroprotective role against A53T &agr;-synuclein toxicity <italic>in vivo</italic>.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Synphilin-1 attenuates neuronal degeneration in the A53T -synuclein transgenic mouse model</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Synphilin-1 attenuates neuronal degeneration in the A53T -synuclein transgenic mouse model</title></titleInfo><name type="personal"><namePart type="given">Wanli W.</namePart><namePart type="family">Smith</namePart><affiliation></affiliation><affiliation></affiliation><affiliation>E-mail: wsmith@rx.umaryland.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Zhaohui</namePart><namePart type="family">Liu</namePart><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yideng</namePart><namePart type="family">Liang</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Naoki</namePart><namePart type="family">Masuda</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Debbie A.</namePart><namePart type="family">Swing</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nancy A.</namePart><namePart type="family">Jenkins</namePart><affiliation></affiliation><description>Present address: Institute of Molecular and Cell Biology, Singapore, 138673.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Neal G.</namePart><namePart type="family">Copeland</namePart><affiliation></affiliation><description>Present address: Institute of Molecular and Cell Biology, Singapore, 138673.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Juan C.</namePart><namePart type="family">Troncoso</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mikhail</namePart><namePart type="family">Pletnikov</namePart><affiliation></affiliation><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ted M.</namePart><namePart type="family">Dawson</namePart><affiliation></affiliation><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lee J.</namePart><namePart type="family">Martin</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Timothy H.</namePart><namePart type="family">Moran</namePart><affiliation>7, USA,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael K.</namePart><namePart type="family">Lee</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David R.</namePart><namePart type="family">Borchelt</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christopher A.</namePart><namePart type="family">Ross</namePart><affiliation></affiliation><affiliation></affiliation><affiliation></affiliation><affiliation></affiliation><affiliation></affiliation><affiliation>E-mail: wsmith@rx.umaryland.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">2010-06-01</dateIssued><dateCreated encoding="w3cdtf">2010-02-25</dateCreated><copyrightDate encoding="w3cdtf">2010</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>Genetic alterations in -synuclein cause autosomal dominant familial Parkinsonism and may contribute to sporadic Parkinson's disease (PD). Synphilin-1 is an -synuclein-interacting protein, with implications in PD pathogenesis related to protein aggregation. Currently, the in vivo role of synphilin-1 in -synuclein-linked pathogenesis is not fully understood. Using the mouse prion protein promoter, we generated synphilin-1 transgenic mice, which did not display PD-like phenotypes. However, synphilin-1/A53T -synuclein double-transgenic mice survived longer than A53T -synuclein single-transgenic mice. There were attenuated A53T -synuclein-induced motor abnormalities and decreased astroglial reaction and neuronal degeneration in brains in double-transgenic mice. Overexpression of synphilin-1 decreased caspase-3 activation, increased beclin-1 and LC3 II expression and promoted formation of aggresome-like structures, suggesting that synphilin-1 alters multiple cellular pathways to protect against neuronal degeneration. These studies demonstrate that synphilin-1 can diminish the severity of -synucleinopathy and play a neuroprotective role against A53T -synuclein toxicity in vivo.</abstract><note type="footnotes">Present address: Institute of Molecular and Cell Biology, Singapore, 138673.</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>2010</date><detail type="volume"><caption>vol.</caption><number>19</number></detail><detail type="issue"><caption>no.</caption><number>11</number></detail><extent unit="pages"><start>2087</start><end>2098</end></extent></part></relatedItem><identifier type="istex">09A00FB694C02AD73462BB3EC858266D3FAB70D7</identifier><identifier type="DOI">10.1093/hmg/ddq086</identifier><identifier type="ArticleID">ddq086</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2010. 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