Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress
Identifieur interne : 000D39 ( Main/Corpus ); précédent : 000D38; suivant : 000D40Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress
Auteurs : Darren J. Moore ; Li Zhang ; Juan Troncoso ; Michael K. Lee ; Nobutaka Hattori ; Yoshikuni Mizuno ; Ted M. Dawson ; Valina L. DawsonSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2005-01-01.
Abstract
The identification of rare monogenic forms of Parkinson's disease (PD) has provided tremendous insight into the molecular pathogenesis of this disorder. Heritable mutations in α-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.
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DOI: 10.1093/hmg/ddi007
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Heritable mutations in α-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Darren J. 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Dawson</name><affiliations><json:string>Institute for Cell Engineering,</json:string><json:string>Department of Neurology,</json:string><json:string>Department of Neuroscience and</json:string><json:string>Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA and</json:string><json:string>E-mail: vdawson@jhmi.edu</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Article</value></json:item></subject><language><json:string>eng</json:string></language><abstract>The identification of rare monogenic forms of Parkinson's disease (PD) has provided tremendous insight into the molecular pathogenesis of this disorder. Heritable mutations in α-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.</abstract><qualityIndicators><score>8</score><pdfVersion>1.2</pdfVersion><pdfPageSize>610 x 795 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>1</keywordCount><abstractCharCount>1772</abstractCharCount><pdfWordCount>9977</pdfWordCount><pdfCharCount>63658</pdfCharCount><pdfPageCount>14</pdfPageCount><abstractWordCount>253</abstractWordCount></qualityIndicators><title>Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress</title><genre><json:string>research-article</json:string></genre><host><volume>14</volume><pages><last>84</last><first>71</first></pages><issn><json:string>0964-6906</json:string></issn><issue>1</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2083</json:string></eissn><title>Human Molecular Genetics</title></host><categories><wos><json:string>BIOCHEMISTRY & MOLECULAR BIOLOGY</json:string><json:string>GENETICS & HEREDITY</json:string></wos></categories><publicationDate>2005</publicationDate><copyrightDate>2005</copyrightDate><doi><json:string>10.1093/hmg/ddi007</json:string></doi><id>5C6DFCC0496BC0E195D5E977470B21E1E2B0A39C</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/5C6DFCC0496BC0E195D5E977470B21E1E2B0A39C/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/5C6DFCC0496BC0E195D5E977470B21E1E2B0A39C/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/5C6DFCC0496BC0E195D5E977470B21E1E2B0A39C/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress</title><respStmt xml:id="ISTEX-API" resp="Références bibliographiques récupérées via GROBID" name="ISTEX-API (INIST-CNRS)"></respStmt></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>OUP</p></availability><date>2004-11-03</date></publicationStmt><notesStmt><note>*To whom correspondence should be addressed at: Department of Neurology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N. 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In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.</p></abstract></profileDesc><revisionDesc><change when="2004-11-03">Created</change><change when="2005-01-01">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/5C6DFCC0496BC0E195D5E977470B21E1E2B0A39C/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="US-ASCII"</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 xml:lang="en" article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">hmg</journal-id><journal-id journal-id-type="nlm-ta">Hum Mol Genet</journal-id><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><abbrev-journal-title abbrev-type="publisher">Hum. Mol. Genet.</abbrev-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="other">ddi007</article-id><article-id pub-id-type="doi">10.1093/hmg/ddi007</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Moore</surname><given-names>Darren J.</given-names></name><xref rid="AF1">1</xref><xref rid="AF2">2</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Li</given-names></name><xref rid="AF1">1</xref><xref rid="AF2">2</xref></contrib><contrib contrib-type="author"><name><surname>Troncoso</surname><given-names>Juan</given-names></name><xref rid="AF2">2</xref><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Michael K.</given-names></name><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Hattori</surname><given-names>Nobutaka</given-names></name><xref rid="AF6">6</xref></contrib><contrib contrib-type="author"><name><surname>Mizuno</surname><given-names>Yoshikuni</given-names></name><xref rid="AF6">6</xref></contrib><contrib contrib-type="author"><name><surname>Dawson</surname><given-names>Ted M.</given-names></name><xref rid="AF1">1</xref><xref rid="AF4">4</xref></contrib><contrib contrib-type="author"><name><surname>Dawson</surname><given-names>Valina L.</given-names></name><xref rid="AF1">1</xref><xref rid="AF2">2</xref><xref rid="AF4">4</xref><xref rid="AF5">5</xref><xref rid="COR1">*</xref></contrib><aff id="AF1"><sup>1</sup>Institute for Cell Engineering,</aff><aff id="AF2"><sup>2</sup>Department of Neurology,</aff><aff id="AF3"><sup>3</sup>Department of Pathology,</aff><aff id="AF4"><sup>4</sup>Department of Neuroscience and</aff><aff id="AF5"><sup>5</sup>Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA and</aff><aff id="AF6"><sup>6</sup>Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-0033, Japan</aff></contrib-group><author-notes><corresp id="COR1"><label>*</label>To whom correspondence should be addressed at: Department of Neurology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N. Broadway, Suite 731, Baltimore, MD 21205, USA. Tel: +1 4106143359; Fax: +1 4106149568; Email: <ext-link xlink:href="vdawson@jhmi.edu" ext-link-type="email">vdawson@jhmi.edu</ext-link></corresp></author-notes><pub-date pub-type="epub"><day>3</day><month>11</month><year>2004</year></pub-date><pub-date pub-type="ppub"><day>1</day><month>January</month><year>2005</year></pub-date><volume>14</volume><issue>1</issue><fpage>71</fpage><lpage>84</lpage><history><date date-type="accepted"><day>22</day><month>10</month><year>2004</year></date><date date-type="received"><day>6</day><month>06</month><year>2004</year></date><date date-type="rev-recd"><day>11</day><month>08</month><year>2004</year></date></history><permissions><copyright-statement>Human Molecular Genetics, Vol. 14, No. 1 © Oxford University Press 2005; all rights reserved</copyright-statement><copyright-year>2005</copyright-year></permissions><self-uri content-type="arthw-pdf" xlink:href="ddi007"></self-uri><abstract xml:lang="en"><p>The identification of rare monogenic forms of Parkinson's disease (PD) has provided tremendous insight into the molecular pathogenesis of this disorder. Heritable mutations in α-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.</p></abstract><custom-meta-wrap><custom-meta><meta-name>hwp-legacy-fpage</meta-name><meta-value>71</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>1 January 2005</meta-value></custom-meta><custom-meta><meta-name>hwp-legacy-dochead</meta-name><meta-value>Article</meta-value></custom-meta></custom-meta-wrap></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress</title></titleInfo><name type="personal"><namePart type="given">Darren J.</namePart><namePart type="family">Moore</namePart><affiliation>Institute for Cell Engineering,</affiliation><affiliation>Department of Neurology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Li</namePart><namePart type="family">Zhang</namePart><affiliation>Institute for Cell Engineering,</affiliation><affiliation>Department of Neurology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Juan</namePart><namePart type="family">Troncoso</namePart><affiliation>Department of Neurology,</affiliation><affiliation>Department of Pathology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael K.</namePart><namePart type="family">Lee</namePart><affiliation>Department of Pathology,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nobutaka</namePart><namePart type="family">Hattori</namePart><affiliation>Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-0033, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yoshikuni</namePart><namePart type="family">Mizuno</namePart><affiliation>Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-0033, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ted M.</namePart><namePart type="family">Dawson</namePart><affiliation>Institute for Cell Engineering,</affiliation><affiliation>Department of Neuroscience and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Valina L.</namePart><namePart type="family">Dawson</namePart><affiliation>Institute for Cell Engineering,</affiliation><affiliation>Department of Neurology,</affiliation><affiliation>Department of Neuroscience and</affiliation><affiliation>Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA and</affiliation><affiliation>E-mail: vdawson@jhmi.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2005-01-01</dateIssued><dateCreated encoding="w3cdtf">2004-11-03</dateCreated><copyrightDate encoding="w3cdtf">2005</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 lang="en">The identification of rare monogenic forms of Parkinson's disease (PD) has provided tremendous insight into the molecular pathogenesis of this disorder. Heritable mutations in α-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.</abstract><note type="author-notes">*To whom correspondence should be addressed at: Department of Neurology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N. Broadway, Suite 731, Baltimore, MD 21205, USA. 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Genet.</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><identifier type="PublisherID-nlm-ta">Hum Mol Genet</identifier><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>14</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>71</start><end>84</end></extent></part></relatedItem><identifier type="istex">5C6DFCC0496BC0E195D5E977470B21E1E2B0A39C</identifier><identifier type="DOI">10.1093/hmg/ddi007</identifier><identifier type="href">ddi007</identifier><identifier type="local">ddi007</identifier><accessCondition type="use and reproduction" contentType="copyright">Human Molecular Genetics, Vol. 14, No. 1 © Oxford University Press 2005; all rights reserved</accessCondition><recordInfo><recordContentSource>OUP</recordContentSource></recordInfo></mods></metadata><annexes><json:item><original>true</original><mimetype>image/jpeg</mimetype><extension>jpeg</extension><uri>https://api.istex.fr/document/5C6DFCC0496BC0E195D5E977470B21E1E2B0A39C/annexes/jpeg</uri></json:item><json:item><original>true</original><mimetype>image/gif</mimetype><extension>gif</extension><uri>https://api.istex.fr/document/5C6DFCC0496BC0E195D5E977470B21E1E2B0A39C/annexes/gif</uri></json:item></annexes><enrichments><istex:catWosTEI uri="https://api.istex.fr/document/5C6DFCC0496BC0E195D5E977470B21E1E2B0A39C/enrichments/catWos"><teiHeader><profileDesc><textClass><classCode scheme="WOS">BIOCHEMISTRY & MOLECULAR BIOLOGY</classCode><classCode scheme="WOS">GENETICS & HEREDITY</classCode></textClass></profileDesc></teiHeader></istex:catWosTEI></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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