ParkinsonCanadaV1, PascalFrancis, Corpus, bibRecord, 000322

Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease

Identifieur interne : 000322 ( PascalFrancis/Corpus ); précédent : 000321; suivant : 000323

Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease

Auteurs : GUANG SHI ; Jeffrey R. Lee ; David A. Grimes ; Lemuel Racacho ; David Ye ; Howard Yang ; Owen A. Ross ; Matthew Farrer ; G. Angus Mcquibban ; Dennis E. Bulman

Source :

Human molecular genetics : (Print) [ 0964-6906 ] ; 2011.

RBID : Pascal:11-0237654

Descripteurs français

Pascal (Inist)
- Altération, Mitochondrie, Génétique, Maladie de Parkinson.

English descriptors

KwdEn :
- Alteration, Genetics, Mitochondria, Parkinson disease.

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.

Notice en format standard (ISO 2709)

Pour connaître la documentation sur le format Inist Standard.

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C01	`01`		`ENG`	@0 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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Format Inist (serveur)

NO :	PASCAL 11-0237654 INIST
ET :	Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease
AU :	GUANG SHI; LEE (Jeffrey R.); GRIMES (David A.); RACACHO (Lemuel); YE (David); YANG (Howard); ROSS (Owen A.); FARRER (Matthew); MCQUIBBAN (G. Angus); BULMAN (Dennis E.)
AF :	Department of Biochemistry, University of Toronto, 1 King's College Circle/Toronto, ON, M5S 1A8/Canada (1 aut., 2 aut., 5 aut., 9 aut.); Department of Neuroscience, Mayo Clinic/Jacksonville, FL 32224/Etats-Unis (7 aut.); Department of Medical Genetics, University of British Columbia/Vancouver/Canada (8 aut.); Ottawa Hospital Research Institute/Ottawa, ON, K1 H 8L6/Canada (3 aut., 6 aut., 10 aut.); Division of Neurology, Ottawa Hospital and University of Ottawa/Ottawa, ON, XK1Y 4E9/Canada (3 aut., 10 aut.); Department of Biochemistry, Microbiology and Immunology, University of Ottawa/Ottawa, ON, K1 H 8M5/Canada (4 aut., 10 aut.)
DT :	Publication en série; Niveau analytique
SO :	Human molecular genetics : (Print); ISSN 0964-6906; Royaume-Uni; Da. 2011; Vol. 20; No. 10; Pp. 1966-1974; Bibl. 39 ref.
LA :	Anglais
EA :	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.
CC :	002A04; 002A07; 002B17G
FD :	Altération; Mitochondrie; Génétique; Maladie de Parkinson
FG :	Pathologie de l'encéphale; Syndrome extrapyramidal; Maladie dégénérative; Pathologie du système nerveux central; Pathologie du système nerveux
ED :	Alteration; Mitochondria; Genetics; Parkinson disease
EG :	Cerebral disorder; Extrapyramidal syndrome; Degenerative disease; Central nervous system disease; Nervous system diseases
SD :	Alteración; Mitocondria; Genética; Parkinson enfermedad
LO :	INIST-22540.354000191488250090
ID :	11-0237654

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Pascal:11-0237654

Le document en format XML

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<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>
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<ET>Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease</ET>
<AU>GUANG SHI; LEE (Jeffrey R.); GRIMES (David A.); RACACHO (Lemuel); YE (David); YANG (Howard); ROSS (Owen A.); FARRER (Matthew); MCQUIBBAN (G. Angus); BULMAN (Dennis E.)</AU>
<AF>Department of Biochemistry, University of Toronto, 1 King's College Circle/Toronto, ON, M5S 1A8/Canada (1 aut., 2 aut., 5 aut., 9 aut.); Department of Neuroscience, Mayo Clinic/Jacksonville, FL 32224/Etats-Unis (7 aut.); Department of Medical Genetics, University of British Columbia/Vancouver/Canada (8 aut.); Ottawa Hospital Research Institute/Ottawa, ON, K1 H 8L6/Canada (3 aut., 6 aut., 10 aut.); Division of Neurology, Ottawa Hospital and University of Ottawa/Ottawa, ON, XK1Y 4E9/Canada (3 aut., 10 aut.); Department of Biochemistry, Microbiology and Immunology, University of Ottawa/Ottawa, ON, K1 H 8M5/Canada (4 aut., 10 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
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<EA>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.</EA>
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	La maladie de Parkinson au Canada (serveur d'exploration)
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La maladie de Parkinson au Canada (serveur d'exploration)

Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease

Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease

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