TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains
Identifieur interne : 002027 ( Main/Corpus ); précédent : 002026; suivant : 002028TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains
Auteurs : Silvia Zucchelli ; Marta Codrich ; Federica Marcuzzi ; Milena Pinto ; Sandra Vilotti ; Marta Biagioli ; Isidro Ferrer ; Stefano GustincichSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-10-01.
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the Substantia Nigra and the formation of ubiquitin- and alpha-synuclein (aSYN)-positive cytoplasmic inclusions called Lewy bodies (LBs). Although most PD cases are sporadic, families with genetic mutations have been found. Mutations in PARK7/DJ-1 have been associated with autosomal recessive early-onset PD, while missense mutations or duplications of aSYN (PARK1, PARK4) have been linked to dominant forms of the disease. In this study, we identify the E3 ubiquitin ligase tumor necrosis factor-receptor associated factor 6 (TRAF6) as a common player in genetic and sporadic cases. TRAF6 binds misfolded mutant DJ-1 and aSYN. Both proteins are substrates of TRAF6 ligase activity in vivo. Interestingly, rather than conventional K63 assembly, TRAF6 promotes atypical ubiquitin linkage formation to both PD targets that share K6-, K27- and K29- mediated ubiquitination. Importantly, TRAF6 stimulates the accumulation of insoluble and polyubiquitinated mutant DJ-1 into cytoplasmic aggregates. In human post-mortem brains of PD patients, TRAF6 protein colocalizes with aSYN in LBs. These results reveal a novel role for TRAF6 and for atypical ubiquitination in PD pathogenesis.
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DOI: 10.1093/hmg/ddq290
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last="Biagioli">Marta Biagioli</name><affiliation><mods:affiliation>4, Km 163.5, Basovizza, 34012 Trieste, Italy,</mods:affiliation></affiliation><affiliation><mods:affiliation>.5, Basovizza, 34012 Trieste, Italy and</mods:affiliation></affiliation></author><author><name sortKey="Ferrer, Isidro" sort="Ferrer, Isidro" uniqKey="Ferrer I" first="Isidro" last="Ferrer">Isidro Ferrer</name><affiliation><mods:affiliation></mods:affiliation></affiliation></author><author><name sortKey="Gustincich, Stefano" sort="Gustincich, Stefano" uniqKey="Gustincich S" first="Stefano" last="Gustincich">Stefano Gustincich</name><affiliation><mods:affiliation>4, Km 163.5, Basovizza, 34012 Trieste, Italy,</mods:affiliation></affiliation><affiliation><mods:affiliation>Trieste, Italy,</mods:affiliation></affiliation><affiliation><mods:affiliation>.5, Basovizza, 34012 Trieste, Italy and</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: gustinci@sissa.it</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="2010-10-01">2010-10-01</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">19</biblScope><biblScope unit="page" from="3759">3759</biblScope><biblScope unit="page" to="3770">3770</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">C0D77CF7EEB86567CC81DB08D53C0A2B2951200B</idno><idno type="DOI">10.1093/hmg/ddq290</idno><idno type="href">ddq290.pdf</idno><idno type="ArticleID">ddq290</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 a neurodegenerative disorder characterized by loss of dopaminergic neurons in the Substantia Nigra and the formation of ubiquitin- and alpha-synuclein (aSYN)-positive cytoplasmic inclusions called Lewy bodies (LBs). Although most PD cases are sporadic, families with genetic mutations have been found. Mutations in PARK7/DJ-1 have been associated with autosomal recessive early-onset PD, while missense mutations or duplications of aSYN (PARK1, PARK4) have been linked to dominant forms of the disease. In this study, we identify the E3 ubiquitin ligase tumor necrosis factor-receptor associated factor 6 (TRAF6) as a common player in genetic and sporadic cases. TRAF6 binds misfolded mutant DJ-1 and aSYN. Both proteins are substrates of TRAF6 ligase activity in vivo. Interestingly, rather than conventional K63 assembly, TRAF6 promotes atypical ubiquitin linkage formation to both PD targets that share K6-, K27- and K29- mediated ubiquitination. Importantly, TRAF6 stimulates the accumulation of insoluble and polyubiquitinated mutant DJ-1 into cytoplasmic aggregates. In human post-mortem brains of PD patients, TRAF6 protein colocalizes with aSYN in LBs. These results reveal a novel role for TRAF6 and for atypical ubiquitination in PD pathogenesis.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Silvia Zucchelli</name><affiliations><json:string>Sector of Neurobiology, International School for Advanced Studies (SISSA), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy,</json:string><json:string>SISSA Unit, Italian Institute of Technology (IIT), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy,</json:string><json:string>The Giovanni Armenise-Harvard Foundation Laboratory, International School for Advanced Studies (SISSA), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy and</json:string></affiliations></json:item><json:item><name>Marta Codrich</name><affiliations><json:string>Sector of Neurobiology, International School for Advanced Studies (SISSA), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy,</json:string></affiliations></json:item><json:item><name>Federica Marcuzzi</name><affiliations><json:string>Sector of Neurobiology, International School for Advanced Studies (SISSA), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy,</json:string></affiliations></json:item><json:item><name>Milena Pinto</name><affiliations><json:string>Sector of Neurobiology, International School for Advanced Studies (SISSA), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy,</json:string></affiliations></json:item><json:item><name>Sandra Vilotti</name><affiliations><json:string>Sector of Neurobiology, International School for Advanced Studies (SISSA), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy,</json:string></affiliations></json:item><json:item><name>Marta Biagioli</name><affiliations><json:string>Sector of Neurobiology, International School for Advanced Studies (SISSA), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy,</json:string><json:string>The Giovanni Armenise-Harvard Foundation Laboratory, International School for Advanced Studies (SISSA), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy and</json:string></affiliations></json:item><json:item><name>Isidro Ferrer</name><affiliations><json:string>Institute of Neuropathology, Institut d'Investigacio Biomedica de Bellvitge University Hospital Bellvitge, University of Barcelona, 08907 Hospitalet de LLobregat, Spain</json:string></affiliations></json:item><json:item><name>Stefano Gustincich</name><affiliations><json:string>Sector of Neurobiology, International School for Advanced Studies (SISSA), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy,</json:string><json:string>SISSA Unit, Italian Institute of Technology (IIT), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy,</json:string><json:string>The Giovanni Armenise-Harvard Foundation Laboratory, International School for Advanced Studies (SISSA), AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste, Italy and</json:string><json:string>E-mail: gustinci@sissa.it</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 a neurodegenerative disorder characterized by loss of dopaminergic neurons in the Substantia Nigra and the formation of ubiquitin- and alpha-synuclein (aSYN)-positive cytoplasmic inclusions called Lewy bodies (LBs). Although most PD cases are sporadic, families with genetic mutations have been found. Mutations in PARK7/DJ-1 have been associated with autosomal recessive early-onset PD, while missense mutations or duplications of aSYN (PARK1, PARK4) have been linked to dominant forms of the disease. In this study, we identify the E3 ubiquitin ligase tumor necrosis factor-receptor associated factor 6 (TRAF6) as a common player in genetic and sporadic cases. TRAF6 binds misfolded mutant DJ-1 and aSYN. Both proteins are substrates of TRAF6 ligase activity in vivo. Interestingly, rather than conventional K63 assembly, TRAF6 promotes atypical ubiquitin linkage formation to both PD targets that share K6-, K27- and K29- mediated ubiquitination. Importantly, TRAF6 stimulates the accumulation of insoluble and polyubiquitinated mutant DJ-1 into cytoplasmic aggregates. In human post-mortem brains of PD patients, TRAF6 protein colocalizes with aSYN in LBs. 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Although most PD cases are sporadic, families with genetic mutations have been found. Mutations in PARK7/DJ-1 have been associated with autosomal recessive early-onset PD, while missense mutations or duplications of aSYN (PARK1, PARK4) have been linked to dominant forms of the disease. In this study, we identify the E3 ubiquitin ligase tumor necrosis factor-receptor associated factor 6 (TRAF6) as a common player in genetic and sporadic cases. TRAF6 binds misfolded mutant DJ-1 and aSYN. Both proteins are substrates of TRAF6 ligase activity in vivo. Interestingly, rather than conventional K63 assembly, TRAF6 promotes atypical ubiquitin linkage formation to both PD targets that share K6-, K27- and K29- mediated ubiquitination. Importantly, TRAF6 stimulates the accumulation of insoluble and polyubiquitinated mutant DJ-1 into cytoplasmic aggregates. In human post-mortem brains of PD patients, TRAF6 protein colocalizes with aSYN in LBs. These results reveal a novel role for TRAF6 and for atypical ubiquitination in PD pathogenesis.</p></abstract></profileDesc><revisionDesc><change when="2010-07-14">Created</change><change when="2010-10-01">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/C0D77CF7EEB86567CC81DB08D53C0A2B2951200B/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/ddq290</article-id><article-id pub-id-type="publisher-id">ddq290</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Zucchelli</surname><given-names>Silvia</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>Codrich</surname><given-names>Marta</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Marcuzzi</surname><given-names>Federica</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Pinto</surname><given-names>Milena</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Vilotti</surname><given-names>Sandra</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Biagioli</surname><given-names>Marta</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Ferrer</surname><given-names>Isidro</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Gustincich</surname><given-names>Stefano</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="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Sector of Neurobiology</addr-line>, <institution>International School for Advanced Studies (SISSA)</institution>, <addr-line>AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste</addr-line>, <country>Italy</country>,</aff><aff id="af2"><label>2</label><addr-line>SISSA Unit</addr-line>, <institution>Italian Institute of Technology (IIT)</institution>, <addr-line>AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste</addr-line>, <country>Italy</country>,</aff><aff id="af3"><label>3</label><addr-line>The Giovanni Armenise-Harvard Foundation Laboratory</addr-line>, <institution>International School for Advanced Studies (SISSA)</institution>, <addr-line>AREA Science Park, s.s. 14, Km 163.5, Basovizza, 34012 Trieste</addr-line>, <country>Italy</country> and</aff><aff id="af4"><label>4</label><addr-line>Institute of Neuropathology, Institut d'Investigacio Biomedica de Bellvitge – University Hospital Bellvitge</addr-line>, <institution>University of Barcelona</institution>, <addr-line>08907 Hospitalet de LLobregat</addr-line>, <country>Spain</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed. Tel: <phone>+39 0403756505</phone>; Fax: <fax>+39 0403756502</fax>; Email: <email>gustinci@sissa.it</email></corresp></author-notes><pub-date pub-type="ppub"><day>1</day><month>10</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>14</day><month>7</month><year>2010</year></pub-date><volume>19</volume><issue>19</issue><fpage>3759</fpage><lpage>3770</lpage><history><date date-type="received"><day>9</day><month>4</month><year>2010</year></date><date date-type="accepted"><day>7</day><month>7</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><self-uri content-type="pdf" xlink:href="ddq290.pdf"></self-uri><abstract><p>Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the Substantia Nigra and the formation of ubiquitin- and alpha-synuclein (aSYN)-positive cytoplasmic inclusions called Lewy bodies (LBs). Although most PD cases are sporadic, families with genetic mutations have been found. Mutations in PARK7/DJ-1 have been associated with autosomal recessive early-onset PD, while missense mutations or duplications of aSYN (PARK1, PARK4) have been linked to dominant forms of the disease. In this study, we identify the E3 ubiquitin ligase tumor necrosis factor-receptor associated factor 6 (TRAF6) as a common player in genetic and sporadic cases. TRAF6 binds misfolded mutant DJ-1 and aSYN. Both proteins are substrates of TRAF6 ligase activity <italic>in vivo</italic>. Interestingly, rather than conventional K63 assembly, TRAF6 promotes atypical ubiquitin linkage formation to both PD targets that share K6-, K27- and K29- mediated ubiquitination. Importantly, TRAF6 stimulates the accumulation of insoluble and polyubiquitinated mutant DJ-1 into cytoplasmic aggregates. In human post-mortem brains of PD patients, TRAF6 protein colocalizes with aSYN in LBs. These results reveal a novel role for TRAF6 and for atypical ubiquitination in PD pathogenesis.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains</title></titleInfo><name type="personal"><namePart type="given">Silvia</namePart><namePart type="family">Zucchelli</namePart><affiliation>4, Km 163.5, Basovizza, 34012 Trieste, Italy,</affiliation><affiliation>Trieste, Italy,</affiliation><affiliation>.5, Basovizza, 34012 Trieste, Italy and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marta</namePart><namePart type="family">Codrich</namePart><affiliation>4, Km 163.5, Basovizza, 34012 Trieste, Italy,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Federica</namePart><namePart type="family">Marcuzzi</namePart><affiliation>4, Km 163.5, Basovizza, 34012 Trieste, Italy,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Milena</namePart><namePart type="family">Pinto</namePart><affiliation>4, Km 163.5, Basovizza, 34012 Trieste, Italy,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sandra</namePart><namePart type="family">Vilotti</namePart><affiliation>4, Km 163.5, Basovizza, 34012 Trieste, Italy,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marta</namePart><namePart type="family">Biagioli</namePart><affiliation>4, Km 163.5, Basovizza, 34012 Trieste, Italy,</affiliation><affiliation>.5, Basovizza, 34012 Trieste, Italy and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Isidro</namePart><namePart type="family">Ferrer</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stefano</namePart><namePart type="family">Gustincich</namePart><affiliation>4, Km 163.5, Basovizza, 34012 Trieste, Italy,</affiliation><affiliation>Trieste, Italy,</affiliation><affiliation>.5, Basovizza, 34012 Trieste, Italy and</affiliation><affiliation>E-mail: gustinci@sissa.it</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">2010-10-01</dateIssued><dateCreated encoding="w3cdtf">2010-07-14</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 a neurodegenerative disorder characterized by loss of dopaminergic neurons in the Substantia Nigra and the formation of ubiquitin- and alpha-synuclein (aSYN)-positive cytoplasmic inclusions called Lewy bodies (LBs). Although most PD cases are sporadic, families with genetic mutations have been found. Mutations in PARK7/DJ-1 have been associated with autosomal recessive early-onset PD, while missense mutations or duplications of aSYN (PARK1, PARK4) have been linked to dominant forms of the disease. In this study, we identify the E3 ubiquitin ligase tumor necrosis factor-receptor associated factor 6 (TRAF6) as a common player in genetic and sporadic cases. TRAF6 binds misfolded mutant DJ-1 and aSYN. Both proteins are substrates of TRAF6 ligase activity in vivo. Interestingly, rather than conventional K63 assembly, TRAF6 promotes atypical ubiquitin linkage formation to both PD targets that share K6-, K27- and K29- mediated ubiquitination. Importantly, TRAF6 stimulates the accumulation of insoluble and polyubiquitinated mutant DJ-1 into cytoplasmic aggregates. In human post-mortem brains of PD patients, TRAF6 protein colocalizes with aSYN in LBs. These results reveal a novel role for TRAF6 and for atypical ubiquitination in PD pathogenesis.</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>19</number></detail><extent unit="pages"><start>3759</start><end>3770</end></extent></part></relatedItem><identifier type="istex">C0D77CF7EEB86567CC81DB08D53C0A2B2951200B</identifier><identifier type="DOI">10.1093/hmg/ddq290</identifier><identifier type="href">ddq290.pdf</identifier><identifier type="ArticleID">ddq290</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2010. 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