Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease
Identifieur interne : 001945 ( Main/Exploration ); précédent : 001944; suivant : 001946Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease
Auteurs : GUANG SHI [Canada] ; Jeffrey R. Lee [Canada] ; David A. Grimes [Canada] ; Lemuel Racacho [Canada] ; David Ye [Canada] ; Howard Yang [Canada] ; Owen A. Ross [États-Unis] ; Matthew Farrer [Canada] ; G. Angus Mcquibban [Canada] ; Dennis E. Bulman [Canada]Source :
- Human molecular genetics : (Print) [ 0964-6906 ] ; 2011.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Génétique.
English descriptors
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Abstract
Molecular genetics has linked mitochondrial dysfunction to the pathogenesis of Parkinson's disease by the discovery of rare, inherited mutations in gene products that associate with the mitochondria. Mutations in PTEN-induced kinase-1 (PINK1), which encodes a mitochondrial kinase, and PARKIN, encoding an E3 ubiquitin ligase, are the most frequent causes of recessive Parkinson's disease. Recent functional studies have revealed that PINK1 recruits PARKIN to mitochondria to initiate mitophagy, an important autophagic quality control mechanism that rids the cell of damaged mitochondria. PINK1 is post-translationally processed into a cleaved form whose levels are tightly regulated, although the significance of this processing is unknown. Here we demonstrate that the mitochondrial protease presenilin-associated rhomboid-like (PARL) can affect the proteolytic processing of PINK1 and that normal PINK1 localization and stability requires PARL's catalytic activity. PARL deficiency impairs PARKIN recruitment to mitochondria, suggesting PINK1's processing and localization are important in determining its interaction with PARKIN. We sequenced the PARL gene in Parkinson's disease patients and discovered a novel missense mutation in a functional domain of PARL's N-terminus. This PARL mutant is not sufficient to rescue PARKIN recruitment, suggesting that impaired mitophagy may be an underlying mechanism of disease pathogenesis in patients with PARL mutations.
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Lee</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Biochemistry, University of Toronto, 1 King's College Circle</s1><s2>Toronto, ON, M5S 1A8</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, ON, M5S 1A8</wicri:noRegion><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Grimes, David A" sort="Grimes, David A" uniqKey="Grimes D" first="David A." last="Grimes">David A. Grimes</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Ottawa Hospital Research Institute</s1><s2>Ottawa, ON, K1 H 8L6</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Ottawa Hospital Research Institute</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Division of Neurology, Ottawa Hospital and University of Ottawa</s1><s2>Ottawa, ON, XK1Y 4E9</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Ottawa, ON, XK1Y 4E9</wicri:noRegion></affiliation></author><author><name sortKey="Racacho, Lemuel" sort="Racacho, Lemuel" uniqKey="Racacho L" first="Lemuel" last="Racacho">Lemuel Racacho</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Department of Biochemistry, Microbiology and Immunology, University of Ottawa</s1><s2>Ottawa, ON, K1 H 8M5</s2><s3>CAN</s3><sZ>4 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Ottawa, ON, K1 H 8M5</wicri:noRegion></affiliation></author><author><name sortKey="Ye, David" sort="Ye, David" uniqKey="Ye D" first="David" last="Ye">David Ye</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Biochemistry, University of Toronto, 1 King's College Circle</s1><s2>Toronto, ON, M5S 1A8</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, ON, M5S 1A8</wicri:noRegion><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Yang, Howard" sort="Yang, Howard" uniqKey="Yang H" first="Howard" last="Yang">Howard Yang</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Ottawa Hospital Research Institute</s1><s2>Ottawa, ON, K1 H 8L6</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Ottawa Hospital Research Institute</wicri:noRegion></affiliation></author><author><name sortKey="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A." last="Ross">Owen A. Ross</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Neuroscience, Mayo Clinic</s1><s2>Jacksonville, FL 32224</s2><s3>USA</s3><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Jacksonville, FL 32224</wicri:noRegion></affiliation></author><author><name sortKey="Farrer, Matthew" sort="Farrer, Matthew" uniqKey="Farrer M" first="Matthew" last="Farrer">Matthew Farrer</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Department of Medical Genetics, University of British Columbia</s1><s2>Vancouver</s2><s3>CAN</s3><sZ>8 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Vancouver</wicri:noRegion></affiliation></author><author><name sortKey="Mcquibban, G Angus" sort="Mcquibban, G Angus" uniqKey="Mcquibban G" first="G. Angus" last="Mcquibban">G. Angus Mcquibban</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Biochemistry, University of Toronto, 1 King's College Circle</s1><s2>Toronto, ON, M5S 1A8</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, ON, M5S 1A8</wicri:noRegion><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Bulman, Dennis E" sort="Bulman, Dennis E" uniqKey="Bulman D" first="Dennis E." last="Bulman">Dennis E. Bulman</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Ottawa Hospital Research Institute</s1><s2>Ottawa, ON, K1 H 8L6</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Ottawa Hospital Research Institute</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Division of Neurology, Ottawa Hospital and University of Ottawa</s1><s2>Ottawa, ON, XK1Y 4E9</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Ottawa, ON, XK1Y 4E9</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Department of Biochemistry, Microbiology and Immunology, University of Ottawa</s1><s2>Ottawa, ON, K1 H 8M5</s2><s3>CAN</s3><sZ>4 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Ottawa, ON, K1 H 8M5</wicri:noRegion></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>Alteration</term><term>Genetics</term><term>Mitochondria</term><term>Parkinson disease</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Altération</term><term>Mitochondrie</term><term>Génétique</term><term>Maladie de Parkinson</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Molecular genetics has linked mitochondrial dysfunction to the pathogenesis of Parkinson's disease by the discovery of rare, inherited mutations in gene products that associate with the mitochondria. Mutations in PTEN-induced kinase-1 (PINK1), which encodes a mitochondrial kinase, and PARKIN, encoding an E3 ubiquitin ligase, are the most frequent causes of recessive Parkinson's disease. Recent functional studies have revealed that PINK1 recruits PARKIN to mitochondria to initiate mitophagy, an important autophagic quality control mechanism that rids the cell of damaged mitochondria. PINK1 is post-translationally processed into a cleaved form whose levels are tightly regulated, although the significance of this processing is unknown. Here we demonstrate that the mitochondrial protease presenilin-associated rhomboid-like (PARL) can affect the proteolytic processing of PINK1 and that normal PINK1 localization and stability requires PARL's catalytic activity. PARL deficiency impairs PARKIN recruitment to mitochondria, suggesting PINK1's processing and localization are important in determining its interaction with PARKIN. We sequenced the PARL gene in Parkinson's disease patients and discovered a novel missense mutation in a functional domain of PARL's N-terminus. This PARL mutant is not sufficient to rescue PARKIN recruitment, suggesting that impaired mitophagy may be an underlying mechanism of disease pathogenesis in patients with PARL mutations.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Ontario</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><country name="Canada"><region name="Ontario"><name sortKey="Guang Shi" sort="Guang Shi" uniqKey="Guang Shi" last="Guang Shi">GUANG SHI</name></region><name sortKey="Bulman, Dennis E" sort="Bulman, Dennis E" uniqKey="Bulman D" first="Dennis E." last="Bulman">Dennis E. Bulman</name><name sortKey="Bulman, Dennis E" sort="Bulman, Dennis E" uniqKey="Bulman D" first="Dennis E." last="Bulman">Dennis E. Bulman</name><name sortKey="Bulman, Dennis E" sort="Bulman, Dennis E" uniqKey="Bulman D" first="Dennis E." last="Bulman">Dennis E. Bulman</name><name sortKey="Farrer, Matthew" sort="Farrer, Matthew" uniqKey="Farrer M" first="Matthew" last="Farrer">Matthew Farrer</name><name sortKey="Grimes, David A" sort="Grimes, David A" uniqKey="Grimes D" first="David A." last="Grimes">David A. Grimes</name><name sortKey="Grimes, David A" sort="Grimes, David A" uniqKey="Grimes D" first="David A." last="Grimes">David A. Grimes</name><name sortKey="Lee, Jeffrey R" sort="Lee, Jeffrey R" uniqKey="Lee J" first="Jeffrey R." last="Lee">Jeffrey R. Lee</name><name sortKey="Mcquibban, G Angus" sort="Mcquibban, G Angus" uniqKey="Mcquibban G" first="G. Angus" last="Mcquibban">G. Angus Mcquibban</name><name sortKey="Racacho, Lemuel" sort="Racacho, Lemuel" uniqKey="Racacho L" first="Lemuel" last="Racacho">Lemuel Racacho</name><name sortKey="Yang, Howard" sort="Yang, Howard" uniqKey="Yang H" first="Howard" last="Yang">Howard Yang</name><name sortKey="Ye, David" sort="Ye, David" uniqKey="Ye D" first="David" last="Ye">David Ye</name></country><country name="États-Unis"><noRegion><name sortKey="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A." last="Ross">Owen A. Ross</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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