DJ-1 deficient mice demonstrate similar vulnerability to pathogenic Ala53Thr human -syn toxicity
Identifieur interne : 000658 ( Main/Corpus ); précédent : 000657; suivant : 000659DJ-1 deficient mice demonstrate similar vulnerability to pathogenic Ala53Thr human -syn toxicity
Auteurs : Chenere P. Ramsey ; Elpida Tsika ; Harry Ischiropoulos ; Benoit I. GiassonSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-04-15.
Abstract
Parkinson's disease (PD) is the most common neurodegenerative movement disorder. A pathological hallmark of PD is the presence of intraneuronal inclusions composed of fibrillized -synuclein (-syn) in affected brain regions. Mutations in the gene, PARK7, which encodes DJ-1, can cause autosomal recessive early-onset PD. Although DJ-1 has been shown to be involved in diverse biological processes, several in vitro studies suggest that it can inhibit the formation and protect against the effects of -syn aggregation. We previously established and characterized transgenic mice expressing pathogenic Ala53Thr human -syn (M83 mice) that develop extensive -syn pathologies in the neuroaxis resulting in severe motor impairments and eventual fatality. In the current study, we have crossbred M83 mice on a DJ-1 null background (M83-DJnull mice) in efforts to determine the effects of the lack of DJ-1 in these mice. Animals were assessed and compared for survival rate, distribution of -syn inclusions, biochemical properties of -syn protein, demise and function of nigral dopaminergic neurons, and extent of gliosis in the neuroaxis. M83 and M83-DJnull mice displayed a similar onset of disease and pathological changes, and none of the analyses to assess for changes in pathogenesis revealed any significant differences between M83 and M83-DJnull mice. These findings suggest that DJ-1 may not function to directly modulate -syn nor does DJ-1 appear to play a role in protecting against the deleterious effects of expressing pathogenic Ala53Thr -syn in vivo. It is possible that -syn and DJ-1 mutations may lead to PD via independent mechanisms.
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DOI: 10.1093/hmg/ddq017
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Giasson</name><affiliation><mods:affiliation>9104, USA,</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: giassonb@mail.med.upenn.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="2010-04-15">2010-04-15</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="1425">1425</biblScope><biblScope unit="page" to="1437">1437</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">3F93A9736418869E62A5E8211A68D079540B726F</idno><idno type="DOI">10.1093/hmg/ddq017</idno><idno type="ArticleID">ddq017</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">Parkinson's disease (PD) is the most common neurodegenerative movement disorder. A pathological hallmark of PD is the presence of intraneuronal inclusions composed of fibrillized -synuclein (-syn) in affected brain regions. Mutations in the gene, PARK7, which encodes DJ-1, can cause autosomal recessive early-onset PD. Although DJ-1 has been shown to be involved in diverse biological processes, several in vitro studies suggest that it can inhibit the formation and protect against the effects of -syn aggregation. We previously established and characterized transgenic mice expressing pathogenic Ala53Thr human -syn (M83 mice) that develop extensive -syn pathologies in the neuroaxis resulting in severe motor impairments and eventual fatality. In the current study, we have crossbred M83 mice on a DJ-1 null background (M83-DJnull mice) in efforts to determine the effects of the lack of DJ-1 in these mice. Animals were assessed and compared for survival rate, distribution of -syn inclusions, biochemical properties of -syn protein, demise and function of nigral dopaminergic neurons, and extent of gliosis in the neuroaxis. M83 and M83-DJnull mice displayed a similar onset of disease and pathological changes, and none of the analyses to assess for changes in pathogenesis revealed any significant differences between M83 and M83-DJnull mice. These findings suggest that DJ-1 may not function to directly modulate -syn nor does DJ-1 appear to play a role in protecting against the deleterious effects of expressing pathogenic Ala53Thr -syn in vivo. It is possible that -syn and DJ-1 mutations may lead to PD via independent mechanisms.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Chenere P. Ramsey</name><affiliations><json:string>Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA,</json:string></affiliations></json:item><json:item><name>Elpida Tsika</name><affiliations><json:string>The Children's Hospital of Philadelphia Research Institute and</json:string><json:string>Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece</json:string></affiliations></json:item><json:item><name>Harry Ischiropoulos</name><affiliations><json:string>Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA,</json:string><json:string>The Children's Hospital of Philadelphia Research Institute and</json:string><json:string>Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA and</json:string></affiliations></json:item><json:item><name>Benoit I. Giasson</name><affiliations><json:string>Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA,</json:string><json:string>E-mail: giassonb@mail.med.upenn.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>Parkinson's disease (PD) is the most common neurodegenerative movement disorder. A pathological hallmark of PD is the presence of intraneuronal inclusions composed of fibrillized -synuclein (-syn) in affected brain regions. Mutations in the gene, PARK7, which encodes DJ-1, can cause autosomal recessive early-onset PD. Although DJ-1 has been shown to be involved in diverse biological processes, several in vitro studies suggest that it can inhibit the formation and protect against the effects of -syn aggregation. We previously established and characterized transgenic mice expressing pathogenic Ala53Thr human -syn (M83 mice) that develop extensive -syn pathologies in the neuroaxis resulting in severe motor impairments and eventual fatality. In the current study, we have crossbred M83 mice on a DJ-1 null background (M83-DJnull mice) in efforts to determine the effects of the lack of DJ-1 in these mice. Animals were assessed and compared for survival rate, distribution of -syn inclusions, biochemical properties of -syn protein, demise and function of nigral dopaminergic neurons, and extent of gliosis in the neuroaxis. M83 and M83-DJnull mice displayed a similar onset of disease and pathological changes, and none of the analyses to assess for changes in pathogenesis revealed any significant differences between M83 and M83-DJnull mice. These findings suggest that DJ-1 may not function to directly modulate -syn nor does DJ-1 appear to play a role in protecting against the deleterious effects of expressing pathogenic Ala53Thr -syn in vivo. 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A pathological hallmark of PD is the presence of intraneuronal inclusions composed of fibrillized -synuclein (-syn) in affected brain regions. Mutations in the gene, PARK7, which encodes DJ-1, can cause autosomal recessive early-onset PD. Although DJ-1 has been shown to be involved in diverse biological processes, several in vitro studies suggest that it can inhibit the formation and protect against the effects of -syn aggregation. We previously established and characterized transgenic mice expressing pathogenic Ala53Thr human -syn (M83 mice) that develop extensive -syn pathologies in the neuroaxis resulting in severe motor impairments and eventual fatality. In the current study, we have crossbred M83 mice on a DJ-1 null background (M83-DJnull mice) in efforts to determine the effects of the lack of DJ-1 in these mice. Animals were assessed and compared for survival rate, distribution of -syn inclusions, biochemical properties of -syn protein, demise and function of nigral dopaminergic neurons, and extent of gliosis in the neuroaxis. M83 and M83-DJnull mice displayed a similar onset of disease and pathological changes, and none of the analyses to assess for changes in pathogenesis revealed any significant differences between M83 and M83-DJnull mice. These findings suggest that DJ-1 may not function to directly modulate -syn nor does DJ-1 appear to play a role in protecting against the deleterious effects of expressing pathogenic Ala53Thr -syn in vivo. It is possible that -syn and DJ-1 mutations may lead to PD via independent mechanisms.</p></abstract></profileDesc><revisionDesc><change when="2010-01-20">Created</change><change when="2010-04-15">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-15">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/3F93A9736418869E62A5E8211A68D079540B726F/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/ddq017</article-id><article-id pub-id-type="publisher-id">ddq017</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>DJ-1 deficient mice demonstrate similar vulnerability to pathogenic Ala53Thr human &agr;-syn toxicity</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Ramsey</surname><given-names>Chenere P.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Tsika</surname><given-names>Elpida</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Ischiropoulos</surname><given-names>Harry</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></contrib><contrib contrib-type="author"><name><surname>Giasson</surname><given-names>Benoit I.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Department of Pharmacology</addr-line>, <institution>University of Pennsylvania School of Medicine</institution>, <addr-line>Philadelphia, PA 19104</addr-line>, <country>USA</country>,</aff><aff id="af2"><label>2</label><addr-line>The Children's Hospital of Philadelphia Research Institute</addr-line> and</aff><aff id="af3"><label>3</label><addr-line>Department of Pediatrics</addr-line>, <institution>The Children's Hospital of Philadelphia</institution>, <addr-line>Philadelphia, PA 19104</addr-line>, <country>USA</country> and</aff><aff id="af4"><label>4</label><addr-line>Department of Molecular Biology and Genetics</addr-line>, <institution>Democritus University of Thrace</institution>, <addr-line>Alexandroupolis</addr-line>, <country>Greece</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: <addr-line>Department of Pharmacology</addr-line>, <institution>University of Pennsylvania School of Medicine</institution>, <addr-line>125 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6084</addr-line>, <country>USA</country>. Tel: <phone>+1 2155736012</phone>; Fax: <fax>+1 2155732236</fax>; Email: <email>giassonb@mail.med.upenn.edu</email></corresp></author-notes><pub-date pub-type="ppub"><day>15</day><month>4</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>20</day><month>1</month><year>2010</year></pub-date><volume>19</volume><issue>8</issue><fpage>1425</fpage><lpage>1437</lpage><history><date date-type="received"><day>29</day><month>12</month><year>2009</year></date><date date-type="accepted"><day>12</day><month>1</month><year>2010</year></date></history><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><abstract><p>Parkinson's disease (PD) is the most common neurodegenerative movement disorder. A pathological hallmark of PD is the presence of intraneuronal inclusions composed of fibrillized &agr;-synuclein (&agr;-syn) in affected brain regions. Mutations in the gene, <italic>PARK7</italic>, which encodes DJ-1, can cause autosomal recessive early-onset PD. Although DJ-1 has been shown to be involved in diverse biological processes, several <italic>in vitro</italic> studies suggest that it can inhibit the formation and protect against the effects of &agr;-syn aggregation. We previously established and characterized transgenic mice expressing pathogenic Ala53Thr human &agr;-syn (M83 mice) that develop extensive &agr;-syn pathologies in the neuroaxis resulting in severe motor impairments and eventual fatality. In the current study, we have crossbred M83 mice on a DJ-1 null background (M83-DJnull mice) in efforts to determine the effects of the lack of DJ-1 in these mice. Animals were assessed and compared for survival rate, distribution of &agr;-syn inclusions, biochemical properties of &agr;-syn protein, demise and function of nigral dopaminergic neurons, and extent of gliosis in the neuroaxis. M83 and M83-DJnull mice displayed a similar onset of disease and pathological changes, and none of the analyses to assess for changes in pathogenesis revealed any significant differences between M83 and M83-DJnull mice. These findings suggest that DJ-1 may not function to directly modulate &agr;-syn nor does DJ-1 appear to play a role in protecting against the deleterious effects of expressing pathogenic Ala53Thr &agr;-syn <italic>in vivo</italic>. It is possible that &agr;-syn and DJ-1 mutations may lead to PD via independent mechanisms.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>DJ-1 deficient mice demonstrate similar vulnerability to pathogenic Ala53Thr human -syn toxicity</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>DJ-1 deficient mice demonstrate similar vulnerability to pathogenic Ala53Thr human -syn toxicity</title></titleInfo><name type="personal"><namePart type="given">Chenere P.</namePart><namePart type="family">Ramsey</namePart><affiliation>9104, USA,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Elpida</namePart><namePart type="family">Tsika</namePart><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Harry</namePart><namePart type="family">Ischiropoulos</namePart><affiliation>9104, USA,</affiliation><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Benoit I.</namePart><namePart type="family">Giasson</namePart><affiliation>9104, USA,</affiliation><affiliation>E-mail: giassonb@mail.med.upenn.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">2010-04-15</dateIssued><dateCreated encoding="w3cdtf">2010-01-20</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>Parkinson's disease (PD) is the most common neurodegenerative movement disorder. A pathological hallmark of PD is the presence of intraneuronal inclusions composed of fibrillized -synuclein (-syn) in affected brain regions. Mutations in the gene, PARK7, which encodes DJ-1, can cause autosomal recessive early-onset PD. Although DJ-1 has been shown to be involved in diverse biological processes, several in vitro studies suggest that it can inhibit the formation and protect against the effects of -syn aggregation. We previously established and characterized transgenic mice expressing pathogenic Ala53Thr human -syn (M83 mice) that develop extensive -syn pathologies in the neuroaxis resulting in severe motor impairments and eventual fatality. In the current study, we have crossbred M83 mice on a DJ-1 null background (M83-DJnull mice) in efforts to determine the effects of the lack of DJ-1 in these mice. Animals were assessed and compared for survival rate, distribution of -syn inclusions, biochemical properties of -syn protein, demise and function of nigral dopaminergic neurons, and extent of gliosis in the neuroaxis. M83 and M83-DJnull mice displayed a similar onset of disease and pathological changes, and none of the analyses to assess for changes in pathogenesis revealed any significant differences between M83 and M83-DJnull mice. These findings suggest that DJ-1 may not function to directly modulate -syn nor does DJ-1 appear to play a role in protecting against the deleterious effects of expressing pathogenic Ala53Thr -syn in vivo. It is possible that -syn and DJ-1 mutations may lead to PD via independent mechanisms.</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>2010</date><detail type="volume"><caption>vol.</caption><number>19</number></detail><detail type="issue"><caption>no.</caption><number>8</number></detail><extent unit="pages"><start>1425</start><end>1437</end></extent></part></relatedItem><identifier type="istex">3F93A9736418869E62A5E8211A68D079540B726F</identifier><identifier type="DOI">10.1093/hmg/ddq017</identifier><identifier type="ArticleID">ddq017</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2010. Published by Oxford University Press. All rights reserved. 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