Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation
Identifieur interne : 001263 ( Main/Corpus ); précédent : 001262; suivant : 001264Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation
Auteurs : Bernard L. Schneider ; Corey R. Seehus ; Elizabeth E. Capowski ; Patrick Aebischer ; Su-Chun Zhang ; Clive N. SvendsenSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2007-03-15.
Abstract
Missense mutations and extra copies of the -Synuclein gene result in Parkinson disease (PD). Human stem and progenitor cells can be expanded from embryonic tissues and provide a source of non-transformed neural cells to explore the effects of these pathogenic mutations specifically in human nervous tissue. We over-expressed the wild type, A53T and A30P forms of -synuclein in expanded populations of progenitors derived from the human fetal cortex. The protein localized in the nucleus and around microvesicles. Only the A53T form was acutely toxic, suggesting a unique vulnerability of these progenitors to this mutation. Interestingly, constitutive over-expression of wild-type -synuclein progressively impaired the innate ability of progenitors to switch toward gliogenesis at later passages. To explore the effect of -synuclein on neuronal subtypes selectively affected in PD, such as dopaminergic neurons, -synuclein and its mutations were also over-expressed in terminally differentiating neuroectodermal cultures derived from human embryonic stem cells (hESC). Alpha-synuclein induced acute cytotoxicity and reduced the number of neurons expressing either tyrosine hydroxylase or gamma-aminobutyric acid over time. Consistent with the selective vulnerability of ventral midbrain dopaminergic neurons, -synuclein cytotoxicity appeared most pronounced following FGF8/SHH specification and was decreased by inhibition of dopamine synthesis. Together, these data show that -synuclein over-expressed in human neural embryonic cells results in patterns of degeneration that in some cases match features of Parkinson Disease. Thus, neural cells derived from hESC provide a useful model system to understand the development of -synuclein-related pathologies and allow therapeutic drug screening.
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DOI: 10.1093/hmg/ddm008
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Svendsen</name><affiliation><mods:affiliation>500 Highland Avenue, Madison, WI 53705, USA and</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: svendsen@waisman.wisc.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="2007-03-15">2007-03-15</date><biblScope unit="volume">16</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="651">651</biblScope><biblScope unit="page" to="666">666</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">12B4DA26A81EAB2003B04B38575E26CF5D15AF07</idno><idno type="DOI">10.1093/hmg/ddm008</idno><idno type="ArticleID">ddm008</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">Missense mutations and extra copies of the -Synuclein gene result in Parkinson disease (PD). Human stem and progenitor cells can be expanded from embryonic tissues and provide a source of non-transformed neural cells to explore the effects of these pathogenic mutations specifically in human nervous tissue. We over-expressed the wild type, A53T and A30P forms of -synuclein in expanded populations of progenitors derived from the human fetal cortex. The protein localized in the nucleus and around microvesicles. Only the A53T form was acutely toxic, suggesting a unique vulnerability of these progenitors to this mutation. Interestingly, constitutive over-expression of wild-type -synuclein progressively impaired the innate ability of progenitors to switch toward gliogenesis at later passages. To explore the effect of -synuclein on neuronal subtypes selectively affected in PD, such as dopaminergic neurons, -synuclein and its mutations were also over-expressed in terminally differentiating neuroectodermal cultures derived from human embryonic stem cells (hESC). Alpha-synuclein induced acute cytotoxicity and reduced the number of neurons expressing either tyrosine hydroxylase or gamma-aminobutyric acid over time. Consistent with the selective vulnerability of ventral midbrain dopaminergic neurons, -synuclein cytotoxicity appeared most pronounced following FGF8/SHH specification and was decreased by inhibition of dopamine synthesis. Together, these data show that -synuclein over-expressed in human neural embryonic cells results in patterns of degeneration that in some cases match features of Parkinson Disease. Thus, neural cells derived from hESC provide a useful model system to understand the development of -synuclein-related pathologies and allow therapeutic drug screening.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Bernard L. 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Capowski</name><affiliations><json:string>Waisman Center and Department of Anatomy, University of Wisconsin, 1500 Highland Avenue, Madison, WI 53705, USA and</json:string></affiliations></json:item><json:item><name>Patrick Aebischer</name><affiliations><json:string>Brain & Mind Institute, Ecole Polytechnique Fdrale de Lausanne (EPFL), Switzerland</json:string></affiliations></json:item><json:item><name>Su-Chun Zhang</name><affiliations><json:string>Waisman Center and Department of Anatomy, University of Wisconsin, 1500 Highland Avenue, Madison, WI 53705, USA and</json:string></affiliations></json:item><json:item><name>Clive N. 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Only the A53T form was acutely toxic, suggesting a unique vulnerability of these progenitors to this mutation. Interestingly, constitutive over-expression of wild-type -synuclein progressively impaired the innate ability of progenitors to switch toward gliogenesis at later passages. To explore the effect of -synuclein on neuronal subtypes selectively affected in PD, such as dopaminergic neurons, -synuclein and its mutations were also over-expressed in terminally differentiating neuroectodermal cultures derived from human embryonic stem cells (hESC). Alpha-synuclein induced acute cytotoxicity and reduced the number of neurons expressing either tyrosine hydroxylase or gamma-aminobutyric acid over time. Consistent with the selective vulnerability of ventral midbrain dopaminergic neurons, -synuclein cytotoxicity appeared most pronounced following FGF8/SHH specification and was decreased by inhibition of dopamine synthesis. Together, these data show that -synuclein over-expressed in human neural embryonic cells results in patterns of degeneration that in some cases match features of Parkinson Disease. 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Human stem and progenitor cells can be expanded from embryonic tissues and provide a source of non-transformed neural cells to explore the effects of these pathogenic mutations specifically in human nervous tissue. We over-expressed the wild type, A53T and A30P forms of -synuclein in expanded populations of progenitors derived from the human fetal cortex. The protein localized in the nucleus and around microvesicles. Only the A53T form was acutely toxic, suggesting a unique vulnerability of these progenitors to this mutation. Interestingly, constitutive over-expression of wild-type -synuclein progressively impaired the innate ability of progenitors to switch toward gliogenesis at later passages. To explore the effect of -synuclein on neuronal subtypes selectively affected in PD, such as dopaminergic neurons, -synuclein and its mutations were also over-expressed in terminally differentiating neuroectodermal cultures derived from human embryonic stem cells (hESC). Alpha-synuclein induced acute cytotoxicity and reduced the number of neurons expressing either tyrosine hydroxylase or gamma-aminobutyric acid over time. Consistent with the selective vulnerability of ventral midbrain dopaminergic neurons, -synuclein cytotoxicity appeared most pronounced following FGF8/SHH specification and was decreased by inhibition of dopamine synthesis. Together, these data show that -synuclein over-expressed in human neural embryonic cells results in patterns of degeneration that in some cases match features of Parkinson Disease. Thus, neural cells derived from hESC provide a useful model system to understand the development of -synuclein-related pathologies and allow therapeutic drug screening.</p></abstract><textClass><keywords scheme="keyword"><list><item><term>ARTICLES</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2007-02-19">Created</change><change when="2007-03-15">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/12B4DA26A81EAB2003B04B38575E26CF5D15AF07/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">hmg</journal-id><journal-id journal-id-type="publisher-id">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/ddm008</article-id><article-id pub-id-type="publisher-id">ddm008</article-id><article-categories><subj-group><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Schneider</surname><given-names>Bernard L.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Seehus</surname><given-names>Corey R.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Capowski</surname><given-names>Elizabeth E.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Aebischer</surname><given-names>Patrick</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Su-Chun</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Svendsen</surname><given-names>Clive N.</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>Waisman Center and Department of Anatomy</addr-line>, <institution>University of Wisconsin</institution>, <addr-line>1500 Highland Avenue, Madison, WI 53705</addr-line>, <country>USA</country> and</aff><aff id="af2"><label>2</label><institution>Brain & Mind Institute</institution>, <addr-line>Ecole Polytechnique Fédérale de Lausanne (EPFL)</addr-line>, <country>Switzerland</country></aff><author-notes><corresp id="cor1"><label>*</label>correspondence should be addressed. Tel: <phone>+1 6082658668</phone>; Fax: <fax>+1 6082635267</fax>; Email: <email>svendsen@waisman.wisc.edu</email></corresp></author-notes><pub-date pub-type="ppub"><day>15</day><month>March</month><year>2007</year></pub-date><pub-date pub-type="epub"><day>19</day><month>2</month><year>2007</year></pub-date><volume>16</volume><issue>6</issue><fpage>651</fpage><lpage>666</lpage><history><date date-type="received"><day>4</day><month>12</month><year>2006</year></date><date date-type="rev-recd"><day>29</day><month>1</month><year>2007</year></date><date date-type="accepted"><day>30</day><month>1</month><year>2007</year></date></history><copyright-statement>© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2007</copyright-year><abstract><p>Missense mutations and extra copies of the α-<italic>Synuclein</italic> gene result in Parkinson disease (PD). Human stem and progenitor cells can be expanded from embryonic tissues and provide a source of non-transformed neural cells to explore the effects of these pathogenic mutations specifically in human nervous tissue. We over-expressed the wild type, A53T and A30P forms of α-synuclein in expanded populations of progenitors derived from the human fetal cortex. The protein localized in the nucleus and around microvesicles. Only the A53T form was acutely toxic, suggesting a unique vulnerability of these progenitors to this mutation. Interestingly, constitutive over-expression of wild-type α-synuclein progressively impaired the innate ability of progenitors to switch toward gliogenesis at later passages. To explore the effect of α-synuclein on neuronal subtypes selectively affected in PD, such as dopaminergic neurons, α-synuclein and its mutations were also over-expressed in terminally differentiating neuroectodermal cultures derived from human embryonic stem cells (hESC). Alpha-synuclein induced acute cytotoxicity and reduced the number of neurons expressing either tyrosine hydroxylase or gamma-aminobutyric acid over time. Consistent with the selective vulnerability of ventral midbrain dopaminergic neurons, α-synuclein cytotoxicity appeared most pronounced following FGF8/SHH specification and was decreased by inhibition of dopamine synthesis. Together, these data show that α-synuclein over-expressed in human neural embryonic cells results in patterns of degeneration that in some cases match features of Parkinson Disease. Thus, neural cells derived from hESC provide a useful model system to understand the development of α-synuclein-related pathologies and allow therapeutic drug screening.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation</title></titleInfo><name type="personal"><namePart type="given">Bernard L.</namePart><namePart type="family">Schneider</namePart><affiliation>500 Highland Avenue, Madison, WI 53705, USA and</affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Corey R.</namePart><namePart type="family">Seehus</namePart><affiliation>500 Highland Avenue, Madison, WI 53705, USA and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Elizabeth E.</namePart><namePart type="family">Capowski</namePart><affiliation>500 Highland Avenue, Madison, WI 53705, USA and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Patrick</namePart><namePart type="family">Aebischer</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Su-Chun</namePart><namePart type="family">Zhang</namePart><affiliation>500 Highland Avenue, Madison, WI 53705, USA and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Clive N.</namePart><namePart type="family">Svendsen</namePart><affiliation>500 Highland Avenue, Madison, WI 53705, USA and</affiliation><affiliation>E-mail: svendsen@waisman.wisc.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><subject><topic>ARTICLES</topic></subject><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2007-03-15</dateIssued><dateCreated encoding="w3cdtf">2007-02-19</dateCreated><copyrightDate encoding="w3cdtf">2007</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>Missense mutations and extra copies of the -Synuclein gene result in Parkinson disease (PD). Human stem and progenitor cells can be expanded from embryonic tissues and provide a source of non-transformed neural cells to explore the effects of these pathogenic mutations specifically in human nervous tissue. We over-expressed the wild type, A53T and A30P forms of -synuclein in expanded populations of progenitors derived from the human fetal cortex. The protein localized in the nucleus and around microvesicles. Only the A53T form was acutely toxic, suggesting a unique vulnerability of these progenitors to this mutation. Interestingly, constitutive over-expression of wild-type -synuclein progressively impaired the innate ability of progenitors to switch toward gliogenesis at later passages. To explore the effect of -synuclein on neuronal subtypes selectively affected in PD, such as dopaminergic neurons, -synuclein and its mutations were also over-expressed in terminally differentiating neuroectodermal cultures derived from human embryonic stem cells (hESC). Alpha-synuclein induced acute cytotoxicity and reduced the number of neurons expressing either tyrosine hydroxylase or gamma-aminobutyric acid over time. Consistent with the selective vulnerability of ventral midbrain dopaminergic neurons, -synuclein cytotoxicity appeared most pronounced following FGF8/SHH specification and was decreased by inhibition of dopamine synthesis. Together, these data show that -synuclein over-expressed in human neural embryonic cells results in patterns of degeneration that in some cases match features of Parkinson Disease. Thus, neural cells derived from hESC provide a useful model system to understand the development of -synuclein-related pathologies and allow therapeutic drug screening.</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>2007</date><detail type="volume"><caption>vol.</caption><number>16</number></detail><detail type="issue"><caption>no.</caption><number>6</number></detail><extent unit="pages"><start>651</start><end>666</end></extent></part></relatedItem><identifier type="istex">12B4DA26A81EAB2003B04B38575E26CF5D15AF07</identifier><identifier type="DOI">10.1093/hmg/ddm008</identifier><identifier type="ArticleID">ddm008</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2007. Published by Oxford University Press. All rights reserved. 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