Co‐expression of C‐terminal truncated alpha‐synuclein enhances full‐length alpha‐synuclein‐induced pathology
Identifieur interne : 001857 ( Main/Corpus ); précédent : 001856; suivant : 001858Co‐expression of C‐terminal truncated alpha‐synuclein enhances full‐length alpha‐synuclein‐induced pathology
Auteurs : Ayse Ulusoy ; Fabia Febbraro ; Poul H. Jensen ; Deniz Kirik ; Marina Romero-RamosSource :
- European Journal of Neuroscience [ 0953-816X ] ; 2010-08.
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Abstract
Lewy bodies, which are a pathological hallmark of Parkinson’s disease, contain insoluble polymers of alpha‐synuclein (αsyn). Among the different modifications that can promote the formation of toxic αsyn species, C‐terminal truncation is among the most abundant alterations in patients with Parkinson’s disease. In vitro, C‐terminal truncated αsyn aggregates faster and sub‐stoichiometric amounts of C‐terminal truncated αsyn promote aggregation of the full‐length αsyn (αsynFL) and induce neuronal toxicity. To address in vivo the putative stimulation of αsyn‐induced pathology by the presence of truncated αsyn, we used recombinant adeno‐associated virus to express either αsynFL or a C‐terminal truncated αsyn (1‐110) in rats. We adjusted the recombinant adeno‐associated virus vector concentrations so that either protein alone led to only mild to moderate axonal pathology in the terminals of nigrostriatal dopamine neurons without frank cell loss. When these two forms of αsyn were co‐expressed at these pre‐determined levels, it resulted in a more aggressive pathology in fiber terminals as well as dopaminergic cell loss in the substantia nigra. Using an antibody that did not detect the C‐terminal truncated αsyn (1‐110) but only αsynFL, we demonstrated that the co‐expressed truncated protein promoted the progressive accumulation of αsynFL and formation of larger pathological accumulations. Moreover, in the co‐expression group, three of the eight animals showed apomorphine‐induced turning, suggesting prominent post‐synaptic alterations due to impairments in the dopamine release, whereas the mild pathology induced by either form alone did not cause motor abnormalities. Taken together these data suggest that C‐terminal truncated αsyn can interact with and exacerbate the formation of pathological accumulations containing αsynFL in vivo.
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DOI: 10.1111/j.1460-9568.2010.07284.x
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Jensen</name><affiliation><mods:affiliation>Department of Medical Biochemistry, Building 1170, University of Aarhus, Aarhus C DK‐8000, Denmark</mods:affiliation></affiliation></author><author><name sortKey="Kirik, Deniz" sort="Kirik, Deniz" uniqKey="Kirik D" first="Deniz" last="Kirik">Deniz Kirik</name><affiliation><mods:affiliation>Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184, Lund, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Romero Amos, Marina" sort="Romero Amos, Marina" uniqKey="Romero Amos M" first="Marina" last="Romero-Ramos">Marina Romero-Ramos</name><affiliation><mods:affiliation>Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184, Lund, Sweden</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Medical Biochemistry, Building 1170, University of Aarhus, Aarhus C DK‐8000, Denmark</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:46196327D2B92380C43445E89271C29E95883045</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1111/j.1460-9568.2010.07284.x</idno><idno type="url">https://api.istex.fr/document/46196327D2B92380C43445E89271C29E95883045/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">001857</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Co‐expression of C‐terminal truncated alpha‐synuclein enhances full‐length alpha‐synuclein‐induced pathology</title><author><name sortKey="Ulusoy, Ayse" sort="Ulusoy, Ayse" uniqKey="Ulusoy A" first="Ayse" last="Ulusoy">Ayse Ulusoy</name><affiliation><mods:affiliation>Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184, Lund, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Febbraro, Fabia" sort="Febbraro, Fabia" uniqKey="Febbraro F" first="Fabia" last="Febbraro">Fabia Febbraro</name><affiliation><mods:affiliation>Department of Medical Biochemistry, Building 1170, University of Aarhus, Aarhus C DK‐8000, Denmark</mods:affiliation></affiliation></author><author><name sortKey="Jensen, Poul H" sort="Jensen, Poul H" uniqKey="Jensen P" first="Poul H." last="Jensen">Poul H. 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Among the different modifications that can promote the formation of toxic αsyn species, C‐terminal truncation is among the most abundant alterations in patients with Parkinson’s disease. In vitro, C‐terminal truncated αsyn aggregates faster and sub‐stoichiometric amounts of C‐terminal truncated αsyn promote aggregation of the full‐length αsyn (αsynFL) and induce neuronal toxicity. To address in vivo the putative stimulation of αsyn‐induced pathology by the presence of truncated αsyn, we used recombinant adeno‐associated virus to express either αsynFL or a C‐terminal truncated αsyn (1‐110) in rats. We adjusted the recombinant adeno‐associated virus vector concentrations so that either protein alone led to only mild to moderate axonal pathology in the terminals of nigrostriatal dopamine neurons without frank cell loss. When these two forms of αsyn were co‐expressed at these pre‐determined levels, it resulted in a more aggressive pathology in fiber terminals as well as dopaminergic cell loss in the substantia nigra. Using an antibody that did not detect the C‐terminal truncated αsyn (1‐110) but only αsynFL, we demonstrated that the co‐expressed truncated protein promoted the progressive accumulation of αsynFL and formation of larger pathological accumulations. Moreover, in the co‐expression group, three of the eight animals showed apomorphine‐induced turning, suggesting prominent post‐synaptic alterations due to impairments in the dopamine release, whereas the mild pathology induced by either form alone did not cause motor abnormalities. Taken together these data suggest that C‐terminal truncated αsyn can interact with and exacerbate the formation of pathological accumulations containing αsynFL in vivo.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Ayse Ulusoy</name><affiliations><json:string>Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184, Lund, Sweden</json:string></affiliations></json:item><json:item><name>Fabia Febbraro</name><affiliations><json:string>Department of Medical Biochemistry, Building 1170, University of Aarhus, Aarhus C DK‐8000, Denmark</json:string></affiliations></json:item><json:item><name>Poul H. 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Among the different modifications that can promote the formation of toxic αsyn species, C‐terminal truncation is among the most abundant alterations in patients with Parkinson’s disease. In vitro, C‐terminal truncated αsyn aggregates faster and sub‐stoichiometric amounts of C‐terminal truncated αsyn promote aggregation of the full‐length αsyn (αsynFL) and induce neuronal toxicity. To address in vivo the putative stimulation of αsyn‐induced pathology by the presence of truncated αsyn, we used recombinant adeno‐associated virus to express either αsynFL or a C‐terminal truncated αsyn (1‐110) in rats. We adjusted the recombinant adeno‐associated virus vector concentrations so that either protein alone led to only mild to moderate axonal pathology in the terminals of nigrostriatal dopamine neurons without frank cell loss. When these two forms of αsyn were co‐expressed at these pre‐determined levels, it resulted in a more aggressive pathology in fiber terminals as well as dopaminergic cell loss in the substantia nigra. Using an antibody that did not detect the C‐terminal truncated αsyn (1‐110) but only αsynFL, we demonstrated that the co‐expressed truncated protein promoted the progressive accumulation of αsynFL and formation of larger pathological accumulations. Moreover, in the co‐expression group, three of the eight animals showed apomorphine‐induced turning, suggesting prominent post‐synaptic alterations due to impairments in the dopamine release, whereas the mild pathology induced by either form alone did not cause motor abnormalities. 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Among the different modifications that can promote the formation of toxic αsyn species, C‐terminal truncation is among the most abundant alterations in patients with Parkinson’s disease. In vitro, C‐terminal truncated αsyn aggregates faster and sub‐stoichiometric amounts of C‐terminal truncated αsyn promote aggregation of the full‐length αsyn (αsynFL) and induce neuronal toxicity. To address in vivo the putative stimulation of αsyn‐induced pathology by the presence of truncated αsyn, we used recombinant adeno‐associated virus to express either αsynFL or a C‐terminal truncated αsyn (1‐110) in rats. We adjusted the recombinant adeno‐associated virus vector concentrations so that either protein alone led to only mild to moderate axonal pathology in the terminals of nigrostriatal dopamine neurons without frank cell loss. When these two forms of αsyn were co‐expressed at these pre‐determined levels, it resulted in a more aggressive pathology in fiber terminals as well as dopaminergic cell loss in the substantia nigra. Using an antibody that did not detect the C‐terminal truncated αsyn (1‐110) but only αsynFL, we demonstrated that the co‐expressed truncated protein promoted the progressive accumulation of αsynFL and formation of larger pathological accumulations. Moreover, in the co‐expression group, three of the eight animals showed apomorphine‐induced turning, suggesting prominent post‐synaptic alterations due to impairments in the dopamine release, whereas the mild pathology induced by either form alone did not cause motor abnormalities. Taken together these data suggest that C‐terminal truncated αsyn can interact with and exacerbate the formation of pathological accumulations containing αsynFL in vivo.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>adeno‐associated virus</term></item><item><term>aggregation</term></item><item><term>dopaminergic cells</term></item><item><term>Parkinson’s disease</term></item><item><term>rat</term></item><item><term>substantia nigra</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2010-08">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/46196327D2B92380C43445E89271C29E95883045/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Blackwell Publishing Ltd</publisherName><publisherLoc>Oxford, UK</publisherLoc></publisherInfo><doi origin="wiley" registered="yes">10.1111/(ISSN)1460-9568</doi><issn type="print">0953-816X</issn><issn type="electronic">1460-9568</issn><idGroup><id type="product" value="EJN"></id><id type="publisherDivision" value="ST"></id></idGroup><titleGroup><title type="main" sort="EUROPEAN JOURNAL OF NEUROSCIENCE">European Journal of Neuroscience</title></titleGroup></publicationMeta><publicationMeta level="part" position="08103"><doi origin="wiley">10.1111/ejn.2010.32.issue-3</doi><numberingGroup><numbering type="journalVolume" number="32">32</numbering><numbering type="journalIssue" number="3">3</numbering></numberingGroup><coverDate startDate="2010-08">August 2010</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="11" status="forIssue"><doi origin="wiley">10.1111/j.1460-9568.2010.07284.x</doi><idGroup><id type="unit" value="EJN7284"></id></idGroup><titleGroup><title type="tocHeading1">NEUROSYSTEMS</title><title type="tocHeading2"> </title></titleGroup><copyright>© The Authors (2010). Journal Compilation © Federation of European Neuroscience Societies and Blackwell Publishing Ltd</copyright><eventGroup><event type="firstOnline" date="2010-08-02"></event><event type="publishedOnlineFinalForm" date="2010-08-02"></event><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:2.3.27 mode:FullText source:FullText result:FullText" date="2010-11-22"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:4.0.1" date="2014-03-12"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-16"></event></eventGroup><numberingGroup><numbering type="pageFirst" number="409">409</numbering><numbering type="pageLast" number="422">422</numbering></numberingGroup><correspondenceTo><lineatedText><line xml:id="c1">Ayse Ulusoy, <sup>1</sup>Brain Repair and Imaging in Neural Systems, as above.
E‐mail: <email>ayse.ulusoy@med.lu.se</email></line><line xml:id="c2">Marina Romero‐Ramos, <sup>2</sup>Department of Medical Biochemistry as above.
E‐mail: <email>mrr@biokemi.au.dk</email></line></lineatedText></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:EJN.EJN7284.pdf"></link></linkGroup></publicationMeta><contentMeta><unparsedEditorialHistory>Received 25 August 2009, revised 15 April 2010, accepted 18 April 2010</unparsedEditorialHistory><countGroup><count type="figureTotal" number="9"></count><count type="tableTotal" number="0"></count></countGroup><titleGroup><title type="main">Co‐expression of C‐terminal truncated alpha‐synuclein enhances full‐length alpha‐synuclein‐induced pathology</title><title type="shortAuthors">A. Ulusoy <i>et al.</i></title><title type="short">C‐terminal truncated alpha‐synuclein enhances pathology</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1"><personName><givenNames>Ayse</givenNames><familyName>Ulusoy</familyName></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a2"><personName><givenNames>Fabia</givenNames><familyName>Febbraro</familyName></personName></creator><creator creatorRole="author" xml:id="cr3" affiliationRef="#a2"><personName><givenNames>Poul H.</givenNames><familyName>Jensen</familyName></personName></creator><creator creatorRole="author" xml:id="cr4" affiliationRef="#a1"><personName><givenNames>Deniz</givenNames><familyName>Kirik</familyName></personName></creator><creator creatorRole="author" xml:id="cr5" affiliationRef="#a1 #a2"><personName><givenNames>Marina</givenNames><familyName>Romero‐Ramos</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="SE"><unparsedAffiliation>Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184, Lund, Sweden</unparsedAffiliation></affiliation><affiliation xml:id="a2" countryCode="DK"><unparsedAffiliation>Department of Medical Biochemistry, Building 1170, University of Aarhus, Aarhus C DK‐8000, Denmark</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">adeno‐associated virus</keyword><keyword xml:id="k2">aggregation</keyword><keyword xml:id="k3">dopaminergic cells</keyword><keyword xml:id="k4">Parkinson’s disease</keyword><keyword xml:id="k5">rat</keyword><keyword xml:id="k6">substantia nigra</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Lewy bodies, which are a pathological hallmark of Parkinson’s disease, contain insoluble polymers of alpha‐synuclein (αsyn). Among the different modifications that can promote the formation of toxic αsyn species, C‐terminal truncation is among the most abundant alterations in patients with Parkinson’s disease. <i>In vitro</i>, C‐terminal truncated αsyn aggregates faster and sub‐stoichiometric amounts of C‐terminal truncated αsyn promote aggregation of the full‐length αsyn (αsynFL) and induce neuronal toxicity. To address <i>in vivo</i> the putative stimulation of αsyn‐induced pathology by the presence of truncated αsyn, we used recombinant adeno‐associated virus to express either αsynFL or a C‐terminal truncated αsyn (1‐110) in rats. We adjusted the recombinant adeno‐associated virus vector concentrations so that either protein alone led to only mild to moderate axonal pathology in the terminals of nigrostriatal dopamine neurons without frank cell loss. When these two forms of αsyn were co‐expressed at these pre‐determined levels, it resulted in a more aggressive pathology in fiber terminals as well as dopaminergic cell loss in the substantia nigra. Using an antibody that did not detect the C‐terminal truncated αsyn (1‐110) but only αsynFL, we demonstrated that the co‐expressed truncated protein promoted the progressive accumulation of αsynFL and formation of larger pathological accumulations. Moreover, in the co‐expression group, three of the eight animals showed apomorphine‐induced turning, suggesting prominent post‐synaptic alterations due to impairments in the dopamine release, whereas the mild pathology induced by either form alone did not cause motor abnormalities. Taken together these data suggest that C‐terminal truncated αsyn can interact with and exacerbate the formation of pathological accumulations containing αsynFL <i>in vivo</i>.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Co‐expression of C‐terminal truncated alpha‐synuclein enhances full‐length alpha‐synuclein‐induced pathology</title></titleInfo><titleInfo type="abbreviated"><title>C‐terminal truncated alpha‐synuclein enhances pathology</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Co‐expression of C‐terminal truncated alpha‐synuclein enhances full‐length alpha‐synuclein‐induced pathology</title></titleInfo><name type="personal"><namePart type="given">Ayse</namePart><namePart type="family">Ulusoy</namePart><affiliation>Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184, Lund, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Fabia</namePart><namePart type="family">Febbraro</namePart><affiliation>Department of Medical Biochemistry, Building 1170, University of Aarhus, Aarhus C DK‐8000, Denmark</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Poul H.</namePart><namePart type="family">Jensen</namePart><affiliation>Department of Medical Biochemistry, Building 1170, University of Aarhus, Aarhus C DK‐8000, Denmark</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Deniz</namePart><namePart type="family">Kirik</namePart><affiliation>Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184, Lund, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marina</namePart><namePart type="family">Romero‐Ramos</namePart><affiliation>Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184, Lund, Sweden</affiliation><affiliation>Department of Medical Biochemistry, Building 1170, University of Aarhus, Aarhus C DK‐8000, Denmark</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><place><placeTerm type="text">Oxford, UK</placeTerm></place><dateIssued encoding="w3cdtf">2010-08</dateIssued><edition>Received 25 August 2009, revised 15 April 2010, accepted 18 April 2010</edition><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">9</extent></physicalDescription><abstract lang="en">Lewy bodies, which are a pathological hallmark of Parkinson’s disease, contain insoluble polymers of alpha‐synuclein (αsyn). Among the different modifications that can promote the formation of toxic αsyn species, C‐terminal truncation is among the most abundant alterations in patients with Parkinson’s disease. In vitro, C‐terminal truncated αsyn aggregates faster and sub‐stoichiometric amounts of C‐terminal truncated αsyn promote aggregation of the full‐length αsyn (αsynFL) and induce neuronal toxicity. To address in vivo the putative stimulation of αsyn‐induced pathology by the presence of truncated αsyn, we used recombinant adeno‐associated virus to express either αsynFL or a C‐terminal truncated αsyn (1‐110) in rats. We adjusted the recombinant adeno‐associated virus vector concentrations so that either protein alone led to only mild to moderate axonal pathology in the terminals of nigrostriatal dopamine neurons without frank cell loss. When these two forms of αsyn were co‐expressed at these pre‐determined levels, it resulted in a more aggressive pathology in fiber terminals as well as dopaminergic cell loss in the substantia nigra. Using an antibody that did not detect the C‐terminal truncated αsyn (1‐110) but only αsynFL, we demonstrated that the co‐expressed truncated protein promoted the progressive accumulation of αsynFL and formation of larger pathological accumulations. Moreover, in the co‐expression group, three of the eight animals showed apomorphine‐induced turning, suggesting prominent post‐synaptic alterations due to impairments in the dopamine release, whereas the mild pathology induced by either form alone did not cause motor abnormalities. Taken together these data suggest that C‐terminal truncated αsyn can interact with and exacerbate the formation of pathological accumulations containing αsynFL in vivo.</abstract><subject lang="en"><genre>Keywords</genre><topic>adeno‐associated virus</topic><topic>aggregation</topic><topic>dopaminergic cells</topic><topic>Parkinson’s disease</topic><topic>rat</topic><topic>substantia nigra</topic></subject><relatedItem type="host"><titleInfo><title>European Journal of Neuroscience</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0953-816X</identifier><identifier type="eISSN">1460-9568</identifier><identifier type="DOI">10.1111/(ISSN)1460-9568</identifier><identifier type="PublisherID">EJN</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>32</number></detail><detail type="issue"><caption>no.</caption><number>3</number></detail><extent unit="pages"><start>409</start><end>422</end></extent></part></relatedItem><identifier type="istex">46196327D2B92380C43445E89271C29E95883045</identifier><identifier type="DOI">10.1111/j.1460-9568.2010.07284.x</identifier><identifier type="ArticleID">EJN7284</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Authors (2010). Journal Compilation © Federation of European Neuroscience Societies and Blackwell Publishing Ltd</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Blackwell Publishing Ltd</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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