Combined kinase inhibition modulates parkin inactivation
Identifieur interne : 000D38 ( Main/Corpus ); précédent : 000D37; suivant : 000D39Combined kinase inhibition modulates parkin inactivation
Auteurs : Elena Rubio De La Torre ; Berta Luzn-Toro ; Irene Forte-Lago ; Adolfo Minguez-Castellanos ; Isidro Ferrer ; Sabine HilfikerSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2009-03-01.
Abstract
Mutations in the parkin gene cause autosomal-recessive, juvenile-onset parkinsonism, and parkin dysfunction may also play a role in the pathogenesis of sporadic Parkinson disease (PD). Although its precise function remains largely unknown, parkin seems to play a neuroprotective role. Several studies indicate that changes in parkin solubility induced by post-translational modifications, such as S-nitrosylation or dopamine modification, comprise one mechanism of parkin inactivation associated with disease. Protein phosphorylation events have recently been linked to the molecular mechanism(s) underlying PD, but the role of this post-translational modification for parkin function has remained unclear. Here we report that compound phosphorylation of parkin by both casein kinase I and cyclin-dependent kinase 5 (cdk5) decreases parkin solubility, leading to its aggregation and inactivation. Combined kinase inhibition partially reverses the aggregative properties of several pathogenic point mutants in cultured cells. Enhanced parkin phosphorylation is detected in distinct brain areas of individuals with sporadic PD and correlates with increases in the levels of p25, the activator of cdk5. These findings indicate that casein kinase I and cdk5 may represent novel combinatorial therapeutic targets for treating PD.
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DOI: 10.1093/hmg/ddn407
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Although its precise function remains largely unknown, parkin seems to play a neuroprotective role. Several studies indicate that changes in parkin solubility induced by post-translational modifications, such as S-nitrosylation or dopamine modification, comprise one mechanism of parkin inactivation associated with disease. Protein phosphorylation events have recently been linked to the molecular mechanism(s) underlying PD, but the role of this post-translational modification for parkin function has remained unclear. Here we report that compound phosphorylation of parkin by both casein kinase I and cyclin-dependent kinase 5 (cdk5) decreases parkin solubility, leading to its aggregation and inactivation. Combined kinase inhibition partially reverses the aggregative properties of several pathogenic point mutants in cultured cells. Enhanced parkin phosphorylation is detected in distinct brain areas of individuals with sporadic PD and correlates with increases in the levels of p25, the activator of cdk5. These findings indicate that casein kinase I and cdk5 may represent novel combinatorial therapeutic targets for treating PD.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Elena Rubio de la Torre</name><affiliations><json:string>Institute of Parasitology and Biomedicine Lpez-Neyra, Consejo Superior de Investigaciones Cientficas (CSIC), Granada, Spain</json:string></affiliations></json:item><json:item><name>Berta Luzn-Toro</name><affiliations><json:string>Institute of Parasitology and Biomedicine Lpez-Neyra, Consejo Superior de Investigaciones Cientficas (CSIC), Granada, Spain</json:string></affiliations></json:item><json:item><name>Irene Forte-Lago</name><affiliations><json:string>Institute of Parasitology and Biomedicine Lpez-Neyra, Consejo Superior de Investigaciones Cientficas (CSIC), Granada, Spain</json:string></affiliations></json:item><json:item><name>Adolfo Minguez-Castellanos</name><affiliations><json:string>Department of Neurology, Virgen de las Nieves University Hospital, Granada, Spain</json:string></affiliations></json:item><json:item><name>Isidro Ferrer</name><affiliations><json:string>Institute of Neuropathology, IDIBELL-University Hospital Bellvitge, University of Barcelona, Llobregat, Spain</json:string></affiliations></json:item><json:item><name>Sabine Hilfiker</name><affiliations><json:string>Institute of Parasitology and Biomedicine Lpez-Neyra, Consejo Superior de Investigaciones Cientficas (CSIC), Granada, Spain</json:string><json:string>E-mail: sabine.hilfiker@ipb.csic.es</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>Mutations in the parkin gene cause autosomal-recessive, juvenile-onset parkinsonism, and parkin dysfunction may also play a role in the pathogenesis of sporadic Parkinson disease (PD). Although its precise function remains largely unknown, parkin seems to play a neuroprotective role. Several studies indicate that changes in parkin solubility induced by post-translational modifications, such as S-nitrosylation or dopamine modification, comprise one mechanism of parkin inactivation associated with disease. Protein phosphorylation events have recently been linked to the molecular mechanism(s) underlying PD, but the role of this post-translational modification for parkin function has remained unclear. Here we report that compound phosphorylation of parkin by both casein kinase I and cyclin-dependent kinase 5 (cdk5) decreases parkin solubility, leading to its aggregation and inactivation. Combined kinase inhibition partially reverses the aggregative properties of several pathogenic point mutants in cultured cells. Enhanced parkin phosphorylation is detected in distinct brain areas of individuals with sporadic PD and correlates with increases in the levels of p25, the activator of cdk5. 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Although its precise function remains largely unknown, parkin seems to play a neuroprotective role. Several studies indicate that changes in parkin solubility induced by post-translational modifications, such as S-nitrosylation or dopamine modification, comprise one mechanism of parkin inactivation associated with disease. Protein phosphorylation events have recently been linked to the molecular mechanism(s) underlying PD, but the role of this post-translational modification for parkin function has remained unclear. Here we report that compound phosphorylation of parkin by both casein kinase I and cyclin-dependent kinase 5 (cdk5) decreases parkin solubility, leading to its aggregation and inactivation. Combined kinase inhibition partially reverses the aggregative properties of several pathogenic point mutants in cultured cells. Enhanced parkin phosphorylation is detected in distinct brain areas of individuals with sporadic PD and correlates with increases in the levels of p25, the activator of cdk5. These findings indicate that casein kinase I and cdk5 may represent novel combinatorial therapeutic targets for treating PD.</p></abstract></profileDesc><revisionDesc><change when="2008-12-02">Created</change><change when="2009-03-01">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/8EF30814B328D9B22835C471B32D3A63786CD43D/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/ddn407</article-id><article-id pub-id-type="publisher-id">ddn407</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Combined kinase inhibition modulates parkin inactivation</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Rubio de la Torre</surname><given-names>Elena</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Luzón-Toro</surname><given-names>Berta</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Forte-Lago</surname><given-names>Irene</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Minguez-Castellanos</surname><given-names>Adolfo</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ferrer</surname><given-names>Isidro</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Hilfiker</surname><given-names>Sabine</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><institution>Institute of Parasitology and Biomedicine ‘López-Neyra’, Consejo Superior de Investigaciones Científicas (CSIC)</institution>, <addr-line>Granada</addr-line>, <country>Spain</country></aff><aff id="af2"><label>2</label><addr-line>Department of Neurology</addr-line>, <institution>Virgen de las Nieves University Hospital</institution>, <addr-line>Granada</addr-line>, <country>Spain</country></aff><aff id="af3"><label>3</label><institution>Institute of Neuropathology, IDIBELL-University Hospital Bellvitge, University of Barcelona</institution>, <addr-line>Llobregat</addr-line>, <country>Spain</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed. Tel: <phone>+34 958181654</phone>; Fax: <fax>+34 958181632</fax>; Email: <email>sabine.hilfiker@ipb.csic.es</email></corresp></author-notes><pub-date pub-type="ppub"><day>1</day><month>3</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>2</day><month>12</month><year>2008</year></pub-date><volume>18</volume><issue>5</issue><fpage>809</fpage><lpage>823</lpage><history><date date-type="received"><day>3</day><month>10</month><year>2008</year></date><date date-type="accepted"><day>30</day><month>11</month><year>2008</year></date></history><copyright-statement>© 2008 The Author(s).</copyright-statement><copyright-year>2009</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.0/uk/"><p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></license><abstract><p>Mutations in the parkin gene cause autosomal-recessive, juvenile-onset parkinsonism, and parkin dysfunction may also play a role in the pathogenesis of sporadic Parkinson disease (PD). Although its precise function remains largely unknown, parkin seems to play a neuroprotective role. Several studies indicate that changes in parkin solubility induced by post-translational modifications, such as S-nitrosylation or dopamine modification, comprise one mechanism of parkin inactivation associated with disease. Protein phosphorylation events have recently been linked to the molecular mechanism(s) underlying PD, but the role of this post-translational modification for parkin function has remained unclear. Here we report that compound phosphorylation of parkin by both casein kinase I and cyclin-dependent kinase 5 (cdk5) decreases parkin solubility, leading to its aggregation and inactivation. Combined kinase inhibition partially reverses the aggregative properties of several pathogenic point mutants in cultured cells. Enhanced parkin phosphorylation is detected in distinct brain areas of individuals with sporadic PD and correlates with increases in the levels of p25, the activator of cdk5. These findings indicate that casein kinase I and cdk5 may represent novel combinatorial therapeutic targets for treating PD.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Combined kinase inhibition modulates parkin inactivation</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Combined kinase inhibition modulates parkin inactivation</title></titleInfo><name type="personal"><namePart type="given">Elena</namePart><namePart type="family">Rubio de la Torre</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Berta</namePart><namePart type="family">Luzn-Toro</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Irene</namePart><namePart type="family">Forte-Lago</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Adolfo</namePart><namePart type="family">Minguez-Castellanos</namePart><affiliation></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">Sabine</namePart><namePart type="family">Hilfiker</namePart><affiliation></affiliation><affiliation>E-mail: sabine.hilfiker@ipb.csic.es</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2009-03-01</dateIssued><dateCreated encoding="w3cdtf">2008-12-02</dateCreated><copyrightDate encoding="w3cdtf">2009</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Mutations in the parkin gene cause autosomal-recessive, juvenile-onset parkinsonism, and parkin dysfunction may also play a role in the pathogenesis of sporadic Parkinson disease (PD). Although its precise function remains largely unknown, parkin seems to play a neuroprotective role. Several studies indicate that changes in parkin solubility induced by post-translational modifications, such as S-nitrosylation or dopamine modification, comprise one mechanism of parkin inactivation associated with disease. Protein phosphorylation events have recently been linked to the molecular mechanism(s) underlying PD, but the role of this post-translational modification for parkin function has remained unclear. Here we report that compound phosphorylation of parkin by both casein kinase I and cyclin-dependent kinase 5 (cdk5) decreases parkin solubility, leading to its aggregation and inactivation. Combined kinase inhibition partially reverses the aggregative properties of several pathogenic point mutants in cultured cells. Enhanced parkin phosphorylation is detected in distinct brain areas of individuals with sporadic PD and correlates with increases in the levels of p25, the activator of cdk5. 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