Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease.
Identifieur interne : 001666 ( Main/Exploration ); précédent : 001665; suivant : 001667Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease.
Auteurs : Guang Shi [Canada] ; Jeffrey R. Lee ; David A. Grimes ; Lemuel Racacho ; David Ye ; Howard Yang ; Owen A. Ross ; Matthew Farrer ; G Angus Mcquibban ; Dennis E. BulmanSource :
- Human molecular genetics [ 1460-2083 ] ; 2011.
English descriptors
- KwdEn :
- Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Enzyme Stability (genetics), Female, HEK293 Cells, Humans, Intracellular Space (metabolism), Male, Metalloproteases (genetics), Metalloproteases (metabolism), Middle Aged, Mitochondria (genetics), Mitochondria (pathology), Mitochondrial Proteins (genetics), Mitochondrial Proteins (metabolism), Molecular Sequence Data, Mutation (genetics), Parkinson Disease (genetics), Parkinson Disease (physiopathology), Protein Kinases (metabolism), Protein Transport (genetics), Sequence Alignment, Ubiquitin-Protein Ligases (metabolism).
- MESH :
- chemical , genetics : Metalloproteases, Mitochondrial Proteins.
- genetics : Enzyme Stability, Mitochondria, Mutation, Parkinson Disease, Protein Transport.
- metabolism : Intracellular Space, Metalloproteases, Mitochondrial Proteins, Protein Kinases, Ubiquitin-Protein Ligases.
- pathology : Mitochondria.
- physiopathology : Parkinson Disease.
- Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Female, HEK293 Cells, Humans, Male, Middle Aged, Molecular Sequence Data, Sequence Alignment.
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.
DOI: 10.1093/hmg/ddr077
PubMed: 21355049
Affiliations:
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Lee</name></author><author><name sortKey="Grimes, David A" sort="Grimes, David A" uniqKey="Grimes D" first="David A" last="Grimes">David A. Grimes</name></author><author><name sortKey="Racacho, Lemuel" sort="Racacho, Lemuel" uniqKey="Racacho L" first="Lemuel" last="Racacho">Lemuel Racacho</name></author><author><name sortKey="Ye, David" sort="Ye, David" uniqKey="Ye D" first="David" last="Ye">David Ye</name></author><author><name sortKey="Yang, Howard" sort="Yang, Howard" uniqKey="Yang H" first="Howard" last="Yang">Howard Yang</name></author><author><name sortKey="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A" last="Ross">Owen A. 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Lee</name></author><author><name sortKey="Grimes, David A" sort="Grimes, David A" uniqKey="Grimes D" first="David A" last="Grimes">David A. Grimes</name></author><author><name sortKey="Racacho, Lemuel" sort="Racacho, Lemuel" uniqKey="Racacho L" first="Lemuel" last="Racacho">Lemuel Racacho</name></author><author><name sortKey="Ye, David" sort="Ye, David" uniqKey="Ye D" first="David" last="Ye">David Ye</name></author><author><name sortKey="Yang, Howard" sort="Yang, Howard" uniqKey="Yang H" first="Howard" last="Yang">Howard Yang</name></author><author><name sortKey="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A" last="Ross">Owen A. Ross</name></author><author><name sortKey="Farrer, Matthew" sort="Farrer, Matthew" uniqKey="Farrer M" first="Matthew" last="Farrer">Matthew Farrer</name></author><author><name sortKey="Mcquibban, G Angus" sort="Mcquibban, G Angus" uniqKey="Mcquibban G" first="G Angus" last="Mcquibban">G Angus Mcquibban</name></author><author><name sortKey="Bulman, Dennis E" sort="Bulman, Dennis E" uniqKey="Bulman D" first="Dennis E" last="Bulman">Dennis E. Bulman</name></author></analytic><series><title level="j">Human molecular genetics</title><idno type="eISSN">1460-2083</idno><imprint><date when="2011" type="published">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Aged</term><term>Aged, 80 and over</term><term>Amino Acid Sequence</term><term>Enzyme Stability (genetics)</term><term>Female</term><term>HEK293 Cells</term><term>Humans</term><term>Intracellular Space (metabolism)</term><term>Male</term><term>Metalloproteases (genetics)</term><term>Metalloproteases (metabolism)</term><term>Middle Aged</term><term>Mitochondria (genetics)</term><term>Mitochondria (pathology)</term><term>Mitochondrial Proteins (genetics)</term><term>Mitochondrial Proteins (metabolism)</term><term>Molecular Sequence Data</term><term>Mutation (genetics)</term><term>Parkinson Disease (genetics)</term><term>Parkinson Disease (physiopathology)</term><term>Protein Kinases (metabolism)</term><term>Protein Transport (genetics)</term><term>Sequence Alignment</term><term>Ubiquitin-Protein Ligases (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Metalloproteases</term><term>Mitochondrial Proteins</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Enzyme Stability</term><term>Mitochondria</term><term>Mutation</term><term>Parkinson Disease</term><term>Protein Transport</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Intracellular Space</term><term>Metalloproteases</term><term>Mitochondrial Proteins</term><term>Protein Kinases</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Mitochondria</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Aged</term><term>Aged, 80 and over</term><term>Amino Acid Sequence</term><term>Female</term><term>HEK293 Cells</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Molecular Sequence Data</term><term>Sequence Alignment</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></country><region><li>Ontario</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><noCountry><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="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="Ross, Owen A" sort="Ross, Owen A" uniqKey="Ross O" first="Owen A" last="Ross">Owen A. Ross</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></noCountry><country name="Canada"><region name="Ontario"><name sortKey="Shi, Guang" sort="Shi, Guang" uniqKey="Shi G" first="Guang" last="Shi">Guang Shi</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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