Phosphorylation does not prompt, nor prevent, the formation of -synuclein toxic species in a rat model of Parkinson's disease
Identifieur interne : 000E92 ( Main/Corpus ); précédent : 000E91; suivant : 000E93Phosphorylation does not prompt, nor prevent, the formation of -synuclein toxic species in a rat model of Parkinson's disease
Auteurs : Samareh Azeredo Da Silveira ; Bernard L. Schneider ; Carmen Cifuentes-Diaz ; Daniel Sage ; Toufik Abbas-Terki ; Takeshi Iwatsubo ; Michal Unser ; Patrick AebischerSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2009-03-01.
Abstract
Phosphorylation is involved in numerous neurodegenerative diseases. In particular, alpha-synuclein is extensively phosphorylated in aggregates in patients suffering from synucleinopathies. However, the share of this modification in the events that lead to the conversion of alpha-synuclein to aggregated toxic species needed to be clarified. The rat model that we developed through rAAV2/6-mediated expression of alpha-synuclein demonstrates a correlation between neurodegeneration and formation of small filamentous alpha-synuclein aggregates. A mutation preventing phosphorylation (S129A) significantly increases alpha-synuclein toxicity and leads to enhanced formation of beta-sheet-rich, proteinase K-resistant aggregates, increased affinity for intracellular membranes, a disarrayed network of neurofilaments and enhanced alpha-synuclein nuclear localization. The expression of a mutation mimicking phosphorylation (S129D) does not lead to dopaminergic cell loss. Nevertheless, fewer but larger aggregates are formed, and signals of apoptosis are also activated in rats expressing the phosphorylation-mimicking form of alpha-synuclein. These observations strongly suggest that phosphorylation does not play an active role in the accumulation of cytotoxic pre-inclusion aggregates. Unexpectedly, the study also demonstrates that constitutive expression of phosphorylation-mimicking forms of alpha-synuclein does not protect from neurodegeneration. The role of phosphorylation at Serine 129 in the early phase of Parkinson's disease is examined, which brings new perspective to therapeutic approaches focusing on the modulation of kinases/phosphatases activity to control alpha-synuclein toxicity.
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DOI: 10.1093/hmg/ddn417
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Schneider</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Cifuentes Diaz, Carmen" sort="Cifuentes Diaz, Carmen" uniqKey="Cifuentes Diaz C" first="Carmen" last="Cifuentes-Diaz">Carmen Cifuentes-Diaz</name><affiliation><mods:affiliation>9, Institut du Fer Moulin, 75005 Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Sage, Daniel" sort="Sage, Daniel" uniqKey="Sage D" first="Daniel" last="Sage">Daniel Sage</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Abbas Terki, Toufik" sort="Abbas Terki, Toufik" uniqKey="Abbas Terki T" first="Toufik" last="Abbas-Terki">Toufik Abbas-Terki</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Iwatsubo, Takeshi" sort="Iwatsubo, Takeshi" uniqKey="Iwatsubo T" first="Takeshi" last="Iwatsubo">Takeshi Iwatsubo</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Unser, Michal" sort="Unser, Michal" uniqKey="Unser M" first="Michal" last="Unser">Michal Unser</name><affiliation><mods:affiliation>9, Institut du Fer Moulin, 75005 Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Aebischer, Patrick" sort="Aebischer, Patrick" uniqKey="Aebischer P" first="Patrick" last="Aebischer">Patrick Aebischer</name><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: patrick.aebischer@epfl.ch</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:7229B24D644FB2469CE22E2081F0E4F7AF037243</idno><date when="2009" year="2009">2009</date><idno type="doi">10.1093/hmg/ddn417</idno><idno type="url">https://api.istex.fr/document/7229B24D644FB2469CE22E2081F0E4F7AF037243/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000E92</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Phosphorylation does not prompt, nor prevent, the formation of -synuclein toxic species in a rat model of Parkinson's disease</title><author><name sortKey="Azeredo Da Silveira, Samareh" sort="Azeredo Da Silveira, Samareh" uniqKey="Azeredo Da Silveira S" first="Samareh" last="Azeredo Da Silveira">Samareh Azeredo Da Silveira</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Schneider, Bernard L" sort="Schneider, Bernard L" uniqKey="Schneider B" first="Bernard L." last="Schneider">Bernard L. 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In particular, alpha-synuclein is extensively phosphorylated in aggregates in patients suffering from synucleinopathies. However, the share of this modification in the events that lead to the conversion of alpha-synuclein to aggregated toxic species needed to be clarified. The rat model that we developed through rAAV2/6-mediated expression of alpha-synuclein demonstrates a correlation between neurodegeneration and formation of small filamentous alpha-synuclein aggregates. A mutation preventing phosphorylation (S129A) significantly increases alpha-synuclein toxicity and leads to enhanced formation of beta-sheet-rich, proteinase K-resistant aggregates, increased affinity for intracellular membranes, a disarrayed network of neurofilaments and enhanced alpha-synuclein nuclear localization. The expression of a mutation mimicking phosphorylation (S129D) does not lead to dopaminergic cell loss. Nevertheless, fewer but larger aggregates are formed, and signals of apoptosis are also activated in rats expressing the phosphorylation-mimicking form of alpha-synuclein. These observations strongly suggest that phosphorylation does not play an active role in the accumulation of cytotoxic pre-inclusion aggregates. Unexpectedly, the study also demonstrates that constitutive expression of phosphorylation-mimicking forms of alpha-synuclein does not protect from neurodegeneration. The role of phosphorylation at Serine 129 in the early phase of Parkinson's disease is examined, which brings new perspective to therapeutic approaches focusing on the modulation of kinases/phosphatases activity to control alpha-synuclein toxicity.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Samareh Azeredo da Silveira</name><affiliations><json:string>Brain Mind Institute</json:string></affiliations></json:item><json:item><name>Bernard L. 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In particular, alpha-synuclein is extensively phosphorylated in aggregates in patients suffering from synucleinopathies. However, the share of this modification in the events that lead to the conversion of alpha-synuclein to aggregated toxic species needed to be clarified. The rat model that we developed through rAAV2/6-mediated expression of alpha-synuclein demonstrates a correlation between neurodegeneration and formation of small filamentous alpha-synuclein aggregates. A mutation preventing phosphorylation (S129A) significantly increases alpha-synuclein toxicity and leads to enhanced formation of beta-sheet-rich, proteinase K-resistant aggregates, increased affinity for intracellular membranes, a disarrayed network of neurofilaments and enhanced alpha-synuclein nuclear localization. The expression of a mutation mimicking phosphorylation (S129D) does not lead to dopaminergic cell loss. Nevertheless, fewer but larger aggregates are formed, and signals of apoptosis are also activated in rats expressing the phosphorylation-mimicking form of alpha-synuclein. These observations strongly suggest that phosphorylation does not play an active role in the accumulation of cytotoxic pre-inclusion aggregates. Unexpectedly, the study also demonstrates that constitutive expression of phosphorylation-mimicking forms of alpha-synuclein does not protect from neurodegeneration. The role of phosphorylation at Serine 129 in the early phase of Parkinson's disease is examined, which brings new perspective to therapeutic approaches focusing on the modulation of kinases/phosphatases activity to control alpha-synuclein toxicity.</abstract><qualityIndicators><score>8.508</score><pdfVersion>1.5</pdfVersion><pdfPageSize>612 x 797.953 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>1</keywordCount><abstractCharCount>1700</abstractCharCount><pdfWordCount>10915</pdfWordCount><pdfCharCount>71114</pdfCharCount><pdfPageCount>16</pdfPageCount><abstractWordCount>209</abstractWordCount></qualityIndicators><title>Phosphorylation does not prompt, nor prevent, the formation of -synuclein toxic species in a rat model of Parkinson's 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work.</note><affiliation>These authors contributed equally to this work.</affiliation><affiliation>9, Institut du Fer Moulin, 75005 Paris, France</affiliation></author><author><persName><forename type="first">Daniel</forename><surname>Sage</surname></persName><note type="biography">These authors contributed equally to this work.</note><affiliation>These authors contributed equally to this work.</affiliation><affiliation></affiliation></author><author><persName><forename type="first">Toufik</forename><surname>Abbas-Terki</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Takeshi</forename><surname>Iwatsubo</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Michal</forename><surname>Unser</surname></persName><affiliation>9, Institut du Fer Moulin, 75005 Paris, France</affiliation></author><author><persName><forename type="first">Patrick</forename><surname>Aebischer</surname></persName><email>patrick.aebischer@epfl.ch</email><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="2009-03-01"></date><biblScope unit="volume">18</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="872">872</biblScope><biblScope unit="page" to="887">887</biblScope></imprint></monogr><idno type="istex">7229B24D644FB2469CE22E2081F0E4F7AF037243</idno><idno type="DOI">10.1093/hmg/ddn417</idno><idno type="ArticleID">ddn417</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2008-12-12</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Phosphorylation is involved in numerous neurodegenerative diseases. In particular, alpha-synuclein is extensively phosphorylated in aggregates in patients suffering from synucleinopathies. However, the share of this modification in the events that lead to the conversion of alpha-synuclein to aggregated toxic species needed to be clarified. The rat model that we developed through rAAV2/6-mediated expression of alpha-synuclein demonstrates a correlation between neurodegeneration and formation of small filamentous alpha-synuclein aggregates. A mutation preventing phosphorylation (S129A) significantly increases alpha-synuclein toxicity and leads to enhanced formation of beta-sheet-rich, proteinase K-resistant aggregates, increased affinity for intracellular membranes, a disarrayed network of neurofilaments and enhanced alpha-synuclein nuclear localization. The expression of a mutation mimicking phosphorylation (S129D) does not lead to dopaminergic cell loss. Nevertheless, fewer but larger aggregates are formed, and signals of apoptosis are also activated in rats expressing the phosphorylation-mimicking form of alpha-synuclein. These observations strongly suggest that phosphorylation does not play an active role in the accumulation of cytotoxic pre-inclusion aggregates. Unexpectedly, the study also demonstrates that constitutive expression of phosphorylation-mimicking forms of alpha-synuclein does not protect from neurodegeneration. The role of phosphorylation at Serine 129 in the early phase of Parkinson's disease is examined, which brings new perspective to therapeutic approaches focusing on the modulation of kinases/phosphatases activity to control alpha-synuclein toxicity.</p></abstract></profileDesc><revisionDesc><change when="2008-12-12">Created</change><change when="2009-03-01">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/7229B24D644FB2469CE22E2081F0E4F7AF037243/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/ddn417</article-id><article-id pub-id-type="publisher-id">ddn417</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Phosphorylation does not prompt, nor prevent, the formation of α-synuclein toxic species in a rat model of Parkinson's disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Azeredo da Silveira</surname><given-names>Samareh</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Schneider</surname><given-names>Bernard L.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Cifuentes-Diaz</surname><given-names>Carmen</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Sage</surname><given-names>Daniel</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Abbas-Terki</surname><given-names>Toufik</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Iwatsubo</surname><given-names>Takeshi</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Unser</surname><given-names>Michaël</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Aebischer</surname><given-names>Patrick</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><institution>Brain Mind Institute</institution></aff><aff id="af2"><label>2</label><institution>Biomedical Imaging Group, Ecole Polytechnique Fédérale de Lausanne (EPFL)</institution>, <addr-line>CH-1015 Lausanne</addr-line>, <country>Switzerland</country></aff><aff id="af3"><label>3</label><institution>INSERM, U839, Institut du Fer à Moulin</institution>, <addr-line>75005 Paris</addr-line>, <country>France</country></aff><aff id="af4"><label>4</label><addr-line>Department of Neuropathology and Neuroscience</addr-line>, <institution>Graduate School of Pharmaceutical Sciences, University of Tokyo</institution>, <addr-line>Tokyo 113-0033</addr-line>, <country>Japan</country></aff><author-notes><fn id="FN1"><label>†</label><p>These authors contributed equally to this work.</p></fn><corresp id="cor1"><label>*</label>To whom correspondence should be addressed. Tel: <phone>+41 216939505</phone>; Fax: <fax>+41 216939520</fax>; Email: <email>patrick.aebischer@epfl.ch</email></corresp></author-notes><pub-date pub-type="ppub"><day>1</day><month>3</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>12</day><month>12</month><year>2008</year></pub-date><volume>18</volume><issue>5</issue><fpage>872</fpage><lpage>887</lpage><history><date date-type="received"><day>23</day><month>9</month><year>2008</year></date><date date-type="accepted"><day>7</day><month>12</month><year>2008</year></date></history><copyright-statement>© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2009</copyright-year><abstract><p>Phosphorylation is involved in numerous neurodegenerative diseases. In particular, alpha-synuclein is extensively phosphorylated in aggregates in patients suffering from synucleinopathies. However, the share of this modification in the events that lead to the conversion of alpha-synuclein to aggregated toxic species needed to be clarified. The rat model that we developed through rAAV2/6-mediated expression of alpha-synuclein demonstrates a correlation between neurodegeneration and formation of small filamentous alpha-synuclein aggregates. A mutation preventing phosphorylation (S129A) significantly increases alpha-synuclein toxicity and leads to enhanced formation of beta-sheet-rich, proteinase K-resistant aggregates, increased affinity for intracellular membranes, a disarrayed network of neurofilaments and enhanced alpha-synuclein nuclear localization. The expression of a mutation mimicking phosphorylation (S129D) does not lead to dopaminergic cell loss. Nevertheless, fewer but larger aggregates are formed, and signals of apoptosis are also activated in rats expressing the phosphorylation-mimicking form of alpha-synuclein. These observations strongly suggest that phosphorylation does not play an active role in the accumulation of cytotoxic pre-inclusion aggregates. Unexpectedly, the study also demonstrates that constitutive expression of phosphorylation-mimicking forms of alpha-synuclein does not protect from neurodegeneration. The role of phosphorylation at Serine 129 in the early phase of Parkinson's disease is examined, which brings new perspective to therapeutic approaches focusing on the modulation of kinases/phosphatases activity to control alpha-synuclein toxicity.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Phosphorylation does not prompt, nor prevent, the formation of -synuclein toxic species in a rat model of Parkinson's disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Phosphorylation does not prompt, nor prevent, the formation of -synuclein toxic species in a rat model of Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Samareh</namePart><namePart type="family">Azeredo da Silveira</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Bernard L.</namePart><namePart type="family">Schneider</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Carmen</namePart><namePart type="family">Cifuentes-Diaz</namePart><affiliation>9, Institut du Fer Moulin, 75005 Paris, France</affiliation><description>These authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daniel</namePart><namePart type="family">Sage</namePart><affiliation></affiliation><description>These authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Toufik</namePart><namePart type="family">Abbas-Terki</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Takeshi</namePart><namePart type="family">Iwatsubo</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michal</namePart><namePart type="family">Unser</namePart><affiliation>9, Institut du Fer Moulin, 75005 Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Patrick</namePart><namePart type="family">Aebischer</namePart><affiliation></affiliation><affiliation>E-mail: patrick.aebischer@epfl.ch</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">2009-03-01</dateIssued><dateCreated encoding="w3cdtf">2008-12-12</dateCreated><copyrightDate encoding="w3cdtf">2009</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Phosphorylation is involved in numerous neurodegenerative diseases. In particular, alpha-synuclein is extensively phosphorylated in aggregates in patients suffering from synucleinopathies. However, the share of this modification in the events that lead to the conversion of alpha-synuclein to aggregated toxic species needed to be clarified. The rat model that we developed through rAAV2/6-mediated expression of alpha-synuclein demonstrates a correlation between neurodegeneration and formation of small filamentous alpha-synuclein aggregates. A mutation preventing phosphorylation (S129A) significantly increases alpha-synuclein toxicity and leads to enhanced formation of beta-sheet-rich, proteinase K-resistant aggregates, increased affinity for intracellular membranes, a disarrayed network of neurofilaments and enhanced alpha-synuclein nuclear localization. The expression of a mutation mimicking phosphorylation (S129D) does not lead to dopaminergic cell loss. Nevertheless, fewer but larger aggregates are formed, and signals of apoptosis are also activated in rats expressing the phosphorylation-mimicking form of alpha-synuclein. These observations strongly suggest that phosphorylation does not play an active role in the accumulation of cytotoxic pre-inclusion aggregates. Unexpectedly, the study also demonstrates that constitutive expression of phosphorylation-mimicking forms of alpha-synuclein does not protect from neurodegeneration. The role of phosphorylation at Serine 129 in the early phase of Parkinson's disease is examined, which brings new perspective to therapeutic approaches focusing on the modulation of kinases/phosphatases activity to control alpha-synuclein toxicity.</abstract><note type="footnotes">These authors contributed equally to this work.</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>2009</date><detail type="volume"><caption>vol.</caption><number>18</number></detail><detail type="issue"><caption>no.</caption><number>5</number></detail><extent unit="pages"><start>872</start><end>887</end></extent></part></relatedItem><identifier type="istex">7229B24D644FB2469CE22E2081F0E4F7AF037243</identifier><identifier type="DOI">10.1093/hmg/ddn417</identifier><identifier type="ArticleID">ddn417</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2008. Published by Oxford University Press. All rights reserved. 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