The Machado-Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability
Identifieur interne : 001911 ( Main/Exploration ); précédent : 001910; suivant : 001912The Machado-Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability
Auteurs : Thomas M. Durcan [Canada] ; Maria Kontogiannea [Canada] ; Thorhildur Thorarinsdottir [Canada] ; Lara Fallon [Canada] ; Aislinn J. Williams [États-Unis] ; Ana Djarmati [États-Unis] ; Tadeu Fantaneanu [Canada] ; Henry L. Paulson [États-Unis] ; Edward A. Fon [Canada]Source :
- Human molecular genetics : (Print) [ 0964-6906 ] ; 2011.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Génétique.
English descriptors
- KwdEn :
Abstract
Machado-Joseph disease (MJD), the most common dominantly inherited ataxia worldwide, is caused by a polyglutamine (polyQ) expansion in the deubiquitinating (DUB) enzyme ataxin-3. Interestingly, MJD can present clinically with features of Parkinsonism. In this study, we identify parkin, an E3 ubiquitin-ligase responsible for a common familial form of Parkinson's disease, as a novel ataxin-3 binding partner. The interaction between ataxin-3 and parkin is direct, involves multiple domains and is greatly enhanced by parkin self-ubiquitination. Moreover, ataxin-3 deubiquitinates parkin directly in vitro and in cells. Compared with wild-type ataxin-3, MJD-linked polyQ-expanded mutant ataxin-3 is more active, possibly owing to its greater efficiency at DUB K27- and K29-linked Ub conjugates on parkin. Remarkably, mutant but not wild-type ataxin-3 promotes the clearance of parkin via the autophagy pathway. The finding is consistent with the reduction in parkin levels observed in the brains of transgenic mice over-expressing polyQ-expanded but not wild-type ataxin-3, raising the intriguing possibility that increased turnover of parkin may contribute to the pathogenesis of MJD and help explain some of its parkinsonian features.
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Durcan</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University</s1><s2>Montreal, Quebec, H3A 2B4</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Kontogiannea, Maria" sort="Kontogiannea, Maria" uniqKey="Kontogiannea M" first="Maria" last="Kontogiannea">Maria Kontogiannea</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University</s1><s2>Montreal, Quebec, H3A 2B4</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Thorarinsdottir, Thorhildur" sort="Thorarinsdottir, Thorhildur" uniqKey="Thorarinsdottir T" first="Thorhildur" last="Thorarinsdottir">Thorhildur Thorarinsdottir</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University</s1><s2>Montreal, Quebec, H3A 2B4</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Fallon, Lara" sort="Fallon, Lara" uniqKey="Fallon L" first="Lara" last="Fallon">Lara Fallon</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University</s1><s2>Montreal, Quebec, H3A 2B4</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Williams, Aislinn J" sort="Williams, Aislinn J" uniqKey="Williams A" first="Aislinn J." last="Williams">Aislinn J. Williams</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Neurology, University of Michigan, 4001 BSRB, 109 Zina Pitcher Place</s1><s2>Ann Arbor, MI 48109</s2><s3>USA</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Ann Arbor, MI 48109</wicri:noRegion></affiliation></author><author><name sortKey="Djarmati, Ana" sort="Djarmati, Ana" uniqKey="Djarmati A" first="Ana" last="Djarmati">Ana Djarmati</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Neurology, University of Michigan, 4001 BSRB, 109 Zina Pitcher Place</s1><s2>Ann Arbor, MI 48109</s2><s3>USA</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Ann Arbor, MI 48109</wicri:noRegion></affiliation></author><author><name sortKey="Fantaneanu, Tadeu" sort="Fantaneanu, Tadeu" uniqKey="Fantaneanu T" first="Tadeu" last="Fantaneanu">Tadeu Fantaneanu</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University</s1><s2>Montreal, Quebec, H3A 2B4</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Paulson, Henry L" sort="Paulson, Henry L" uniqKey="Paulson H" first="Henry L." last="Paulson">Henry L. Paulson</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Neurology, University of Michigan, 4001 BSRB, 109 Zina Pitcher Place</s1><s2>Ann Arbor, MI 48109</s2><s3>USA</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Ann Arbor, MI 48109</wicri:noRegion></affiliation></author><author><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A." last="Fon">Edward A. Fon</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University</s1><s2>Montreal, Quebec, H3A 2B4</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author></analytic><series><title level="j" type="main">Human molecular genetics : (Print)</title><title level="j" type="abbreviated">Hum. mol. genet. : (Print)</title><idno type="ISSN">0964-6906</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Human molecular genetics : (Print)</title><title level="j" type="abbreviated">Hum. mol. genet. : (Print)</title><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Genetics</term><term>Joseph disease</term><term>Mutation</term><term>Regulation(control)</term><term>Spinocerebellar heredodegeneration</term><term>Stability</term><term>Tumor suppressor gene</term><term>Ubiquitination</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Mutation</term><term>Hérédodégénérescence spinocérébelleuse</term><term>Régulation</term><term>Gène suppresseur tumeur</term><term>Stabilité</term><term>Génétique</term><term>Maladie de Joseph</term><term>Association génétique</term><term>Ataxine</term><term>Gène Parkin</term><term>Ubiquitinylation</term><term>Ubiquitination</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Machado-Joseph disease (MJD), the most common dominantly inherited ataxia worldwide, is caused by a polyglutamine (polyQ) expansion in the deubiquitinating (DUB) enzyme ataxin-3. Interestingly, MJD can present clinically with features of Parkinsonism. In this study, we identify parkin, an E3 ubiquitin-ligase responsible for a common familial form of Parkinson's disease, as a novel ataxin-3 binding partner. The interaction between ataxin-3 and parkin is direct, involves multiple domains and is greatly enhanced by parkin self-ubiquitination. Moreover, ataxin-3 deubiquitinates parkin directly in vitro and in cells. Compared with wild-type ataxin-3, MJD-linked polyQ-expanded mutant ataxin-3 is more active, possibly owing to its greater efficiency at DUB K27- and K29-linked Ub conjugates on parkin. Remarkably, mutant but not wild-type ataxin-3 promotes the clearance of parkin via the autophagy pathway. The finding is consistent with the reduction in parkin levels observed in the brains of transgenic mice over-expressing polyQ-expanded but not wild-type ataxin-3, raising the intriguing possibility that increased turnover of parkin may contribute to the pathogenesis of MJD and help explain some of its parkinsonian features.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Québec</li></region><settlement><li>Montréal</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><country name="Canada"><region name="Québec"><name sortKey="Durcan, Thomas M" sort="Durcan, Thomas M" uniqKey="Durcan T" first="Thomas M." last="Durcan">Thomas M. Durcan</name></region><name sortKey="Fallon, Lara" sort="Fallon, Lara" uniqKey="Fallon L" first="Lara" last="Fallon">Lara Fallon</name><name sortKey="Fantaneanu, Tadeu" sort="Fantaneanu, Tadeu" uniqKey="Fantaneanu T" first="Tadeu" last="Fantaneanu">Tadeu Fantaneanu</name><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A." last="Fon">Edward A. Fon</name><name sortKey="Kontogiannea, Maria" sort="Kontogiannea, Maria" uniqKey="Kontogiannea M" first="Maria" last="Kontogiannea">Maria Kontogiannea</name><name sortKey="Thorarinsdottir, Thorhildur" sort="Thorarinsdottir, Thorhildur" uniqKey="Thorarinsdottir T" first="Thorhildur" last="Thorarinsdottir">Thorhildur Thorarinsdottir</name></country><country name="États-Unis"><noRegion><name sortKey="Williams, Aislinn J" sort="Williams, Aislinn J" uniqKey="Williams A" first="Aislinn J." last="Williams">Aislinn J. Williams</name></noRegion><name sortKey="Djarmati, Ana" sort="Djarmati, Ana" uniqKey="Djarmati A" first="Ana" last="Djarmati">Ana Djarmati</name><name sortKey="Paulson, Henry L" sort="Paulson, Henry L" uniqKey="Paulson H" first="Henry L." last="Paulson">Henry L. Paulson</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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