Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease
Identifieur interne : 001947 ( Main/Corpus ); précédent : 001946; suivant : 001948Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease
Auteurs : Beisha Tang ; Hui Xiong ; Ping Sun ; Yuhu Zhang ; Danling Wang ; Zhengmao Hu ; Zanhua Zhu ; Hong Ma ; Qian Pan ; Jia-Hui Xia ; Kun Xia ; Zhuohua ZhangSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2006-06-01.
Abstract
Mutations in genes encoding both DJ-1 and pten-induced kinase 1 (PINK1) are independently linked to autosomal recessive early-onset familial forms of Parkinson's disease (PD). We here report identification of a family with PD patients harboring novel heterozygous missense mutations in both PINK1 and DJ-1 genes encoding DJ-1A39S and PINK1P399L, respectively. In transfected cells, DJ-1 interacts with PINK1. PINK1P399L is less stable than the wild-type protein and is degraded via the ubiquitin-mediated proteasomal pathway. Expression of wild-type DJ-1 increased steady-state levels of PINK1, whereas expression of DJ-1A39S reduced steady-state levels of PINK1. Furthermore, co-expression of wild-type DJ-1 and PINK1 suppresses neurotoxin 1-methyl-4-phenylpyridinium (MPP+)-induced death of dopaminergic SH-SY5Y cells. In contrast, co-expression of PD-associated DJ-1A39S and PINK1P399L significantly potentiated susceptibility of SH-SY5Y cells to MPP+-induced cell death. This study reports the first case of autosomal recessive PD with digenic inheritance and demonstrates that DJ-1 and PINK1 physically associate and collaborate to protect cells against stress via complex formation.
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DOI: 10.1093/hmg/ddl104
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We here report identification of a family with PD patients harboring novel heterozygous missense mutations in both PINK1 and DJ-1 genes encoding DJ-1A39S and PINK1P399L, respectively. In transfected cells, DJ-1 interacts with PINK1. PINK1P399L is less stable than the wild-type protein and is degraded via the ubiquitin-mediated proteasomal pathway. Expression of wild-type DJ-1 increased steady-state levels of PINK1, whereas expression of DJ-1A39S reduced steady-state levels of PINK1. Furthermore, co-expression of wild-type DJ-1 and PINK1 suppresses neurotoxin 1-methyl-4-phenylpyridinium (MPP+)-induced death of dopaminergic SH-SY5Y cells. In contrast, co-expression of PD-associated DJ-1A39S and PINK1P399L significantly potentiated susceptibility of SH-SY5Y cells to MPP+-induced cell death. This study reports the first case of autosomal recessive PD with digenic inheritance and demonstrates that DJ-1 and PINK1 physically associate and collaborate to protect cells against stress via complex formation.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Beisha Tang</name><affiliations><json:string>National Laboratory of Medical Genetics and</json:string><json:string>Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China and</json:string></affiliations></json:item><json:item><name>Hui Xiong</name><affiliations><json:string>Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA</json:string></affiliations></json:item><json:item><name>Ping Sun</name><affiliations><json:string>Burnham Institute for Medical Research, 10901 N. 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Furthermore, co-expression of wild-type DJ-1 and PINK1 suppresses neurotoxin 1-methyl-4-phenylpyridinium (MPP+)-induced death of dopaminergic SH-SY5Y cells. In contrast, co-expression of PD-associated DJ-1A39S and PINK1P399L significantly potentiated susceptibility of SH-SY5Y cells to MPP+-induced cell death. 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Tel: +1 8587136286; Fax: +1 8587136273; Email: benzz@burnham.org</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease</title><author><persName><forename type="first">Beisha</forename><surname>Tang</surname></persName><affiliation>National Laboratory of Medical Genetics and</affiliation><affiliation>Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China and</affiliation></author><author><persName><forename type="first">Hui</forename><surname>Xiong</surname></persName><affiliation>Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA</affiliation></author><author><persName><forename type="first">Ping</forename><surname>Sun</surname></persName><affiliation>Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA</affiliation></author><author><persName><forename type="first">Yuhu</forename><surname>Zhang</surname></persName><affiliation>National Laboratory of Medical Genetics and</affiliation><affiliation>Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China and</affiliation></author><author><persName><forename type="first">Danling</forename><surname>Wang</surname></persName><affiliation>Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA</affiliation></author><author><persName><forename type="first">Zhengmao</forename><surname>Hu</surname></persName><affiliation>National Laboratory of Medical Genetics and</affiliation></author><author><persName><forename type="first">Zanhua</forename><surname>Zhu</surname></persName><affiliation>National Laboratory of Medical Genetics and</affiliation></author><author><persName><forename type="first">Hong</forename><surname>Ma</surname></persName><affiliation>Burnham Institute for Medical Research, 10901 N. 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Genet.</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2006-06-01"></date><biblScope unit="volume">15</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="1816">1816</biblScope><biblScope unit="page" to="1825">1825</biblScope></imprint></monogr><idno type="istex">6723D34A8B3D0892231977F272FB6D6619943804</idno><idno type="DOI">10.1093/hmg/ddl104</idno><idno type="href">ddl104</idno><idno type="local">ddl104</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2006-04-21</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Mutations in genes encoding both DJ-1 and pten-induced kinase 1 (PINK1) are independently linked to autosomal recessive early-onset familial forms of Parkinson's disease (PD). We here report identification of a family with PD patients harboring novel heterozygous missense mutations in both PINK1 and DJ-1 genes encoding DJ-1A39S and PINK1P399L, respectively. In transfected cells, DJ-1 interacts with PINK1. PINK1P399L is less stable than the wild-type protein and is degraded via the ubiquitin-mediated proteasomal pathway. Expression of wild-type DJ-1 increased steady-state levels of PINK1, whereas expression of DJ-1A39S reduced steady-state levels of PINK1. Furthermore, co-expression of wild-type DJ-1 and PINK1 suppresses neurotoxin 1-methyl-4-phenylpyridinium (MPP+)-induced death of dopaminergic SH-SY5Y cells. In contrast, co-expression of PD-associated DJ-1A39S and PINK1P399L significantly potentiated susceptibility of SH-SY5Y cells to MPP+-induced cell death. This study reports the first case of autosomal recessive PD with digenic inheritance and demonstrates that DJ-1 and PINK1 physically associate and collaborate to protect cells against stress via complex formation.</p></abstract></profileDesc><revisionDesc><change when="2006-04-21">Created</change><change when="2006-06-01">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/6723D34A8B3D0892231977F272FB6D6619943804/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">ddl104</article-id><article-id pub-id-type="doi">10.1093/hmg/ddl104</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Tang</surname><given-names>Beisha</given-names></name><xref rid="AF1">1</xref><xref rid="AF2">2</xref></contrib><contrib contrib-type="author"><name><surname>Xiong</surname><given-names>Hui</given-names></name><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Ping</given-names></name><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Yuhu</given-names></name><xref rid="AF1">1</xref><xref rid="AF2">2</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Danling</given-names></name><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Hu</surname><given-names>Zhengmao</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhu</surname><given-names>Zanhua</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ma</surname><given-names>Hong</given-names></name><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Pan</surname><given-names>Qian</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Xia</surname><given-names>Jia-hui</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Xia</surname><given-names>Kun</given-names></name><xref rid="AF1">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Zhuohua</given-names></name><xref rid="AF3">3</xref><xref rid="COR1">*</xref></contrib><aff id="AF1"><sup>1</sup>National Laboratory of Medical Genetics and</aff><aff id="AF2"><sup>2</sup>Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China and</aff><aff id="AF3"><sup>3</sup>Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA</aff></contrib-group><author-notes><corresp id="COR1"><label>*</label>To whom correspondence should be addressed. Tel: +1 8587136286; Fax: +1 8587136273; Email: <ext-link xlink:href="benzz@burnham.org" ext-link-type="email">benzz@burnham.org</ext-link></corresp></author-notes><pub-date pub-type="epub"><day>21</day><month>04</month><year>2006</year></pub-date><pub-date pub-type="ppub"><day>1</day><month>June</month><year>2006</year></pub-date><volume>15</volume><issue>11</issue><fpage>1816</fpage><lpage>1825</lpage><history><date date-type="accepted"><day>12</day><month>04</month><year>2006</year></date><date date-type="received"><day>20</day><month>02</month><year>2006</year></date></history><permissions><copyright-statement>© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2006</copyright-year></permissions><self-uri content-type="arthw-pdf" xlink:href="ddl104"></self-uri><abstract xml:lang="en"><p>Mutations in genes encoding both <italic>DJ-1</italic> and pten-induced kinase 1 (<italic>PINK1</italic>) are independently linked to autosomal recessive early-onset familial forms of Parkinson's disease (PD). We here report identification of a family with PD patients harboring novel heterozygous missense mutations in both <italic>PINK1</italic> and <italic>DJ-1</italic> genes encoding DJ-1A39S and PINK1P399L, respectively. In transfected cells, DJ-1 interacts with PINK1. PINK1P399L is less stable than the wild-type protein and is degraded via the ubiquitin-mediated proteasomal pathway. Expression of wild-type DJ-1 increased steady-state levels of PINK1, whereas expression of DJ-1A39S reduced steady-state levels of PINK1. Furthermore, co-expression of wild-type DJ-1 and PINK1 suppresses neurotoxin 1-methyl-4-phenylpyridinium (MPP<sup>+</sup>)-induced death of dopaminergic SH-SY5Y cells. In contrast, co-expression of PD-associated DJ-1A39S and PINK1P399L significantly potentiated susceptibility of SH-SY5Y cells to MPP<sup>+</sup>-induced cell death. This study reports the first case of autosomal recessive PD with digenic inheritance and demonstrates that DJ-1 and PINK1 physically associate and collaborate to protect cells against stress via complex formation.</p></abstract><custom-meta-wrap><custom-meta><meta-name>hwp-legacy-fpage</meta-name><meta-value>1816</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>1 June 2006</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 PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Beisha</namePart><namePart type="family">Tang</namePart><affiliation>National Laboratory of Medical Genetics and</affiliation><affiliation>Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hui</namePart><namePart type="family">Xiong</namePart><affiliation>Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ping</namePart><namePart type="family">Sun</namePart><affiliation>Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yuhu</namePart><namePart type="family">Zhang</namePart><affiliation>National Laboratory of Medical Genetics and</affiliation><affiliation>Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Danling</namePart><namePart type="family">Wang</namePart><affiliation>Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Zhengmao</namePart><namePart type="family">Hu</namePart><affiliation>National Laboratory of Medical Genetics and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Zanhua</namePart><namePart type="family">Zhu</namePart><affiliation>National Laboratory of Medical Genetics and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hong</namePart><namePart type="family">Ma</namePart><affiliation>Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Qian</namePart><namePart type="family">Pan</namePart><affiliation>National Laboratory of Medical Genetics and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jia-hui</namePart><namePart type="family">Xia</namePart><affiliation>National Laboratory of Medical Genetics and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kun</namePart><namePart type="family">Xia</namePart><affiliation>National Laboratory of Medical Genetics and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Zhuohua</namePart><namePart type="family">Zhang</namePart><affiliation>Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA</affiliation><affiliation>E-mail: benzz@burnham.org</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">2006-06-01</dateIssued><dateCreated encoding="w3cdtf">2006-04-21</dateCreated><copyrightDate encoding="w3cdtf">2006</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">Mutations in genes encoding both DJ-1 and pten-induced kinase 1 (PINK1) are independently linked to autosomal recessive early-onset familial forms of Parkinson's disease (PD). We here report identification of a family with PD patients harboring novel heterozygous missense mutations in both PINK1 and DJ-1 genes encoding DJ-1A39S and PINK1P399L, respectively. In transfected cells, DJ-1 interacts with PINK1. PINK1P399L is less stable than the wild-type protein and is degraded via the ubiquitin-mediated proteasomal pathway. Expression of wild-type DJ-1 increased steady-state levels of PINK1, whereas expression of DJ-1A39S reduced steady-state levels of PINK1. Furthermore, co-expression of wild-type DJ-1 and PINK1 suppresses neurotoxin 1-methyl-4-phenylpyridinium (MPP+)-induced death of dopaminergic SH-SY5Y cells. In contrast, co-expression of PD-associated DJ-1A39S and PINK1P399L significantly potentiated susceptibility of SH-SY5Y cells to MPP+-induced cell death. This study reports the first case of autosomal recessive PD with digenic inheritance and demonstrates that DJ-1 and PINK1 physically associate and collaborate to protect cells against stress via complex formation.</abstract><note type="author-notes">*To whom correspondence should be addressed. Tel: +1 8587136286; Fax: +1 8587136273; Email: benzz@burnham.org</note><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><titleInfo type="abbreviated"><title>Hum. Mol. 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>2006</date><detail type="volume"><caption>vol.</caption><number>15</number></detail><detail type="issue"><caption>no.</caption><number>11</number></detail><extent unit="pages"><start>1816</start><end>1825</end></extent></part></relatedItem><identifier type="istex">6723D34A8B3D0892231977F272FB6D6619943804</identifier><identifier type="DOI">10.1093/hmg/ddl104</identifier><identifier type="href">ddl104</identifier><identifier type="local">ddl104</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Author 2006. Published by Oxford University Press. All rights reserved. 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