title: Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's 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.
authors.affiliation: Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, ON, Canada M5S 1A8.
authors.forename: Guang
authors.initials: G
authors.lastname: Shi
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Lee
authors.forename: David A
authors.initials: DA
authors.lastname: Grimes
authors.forename: Lemuel
authors.initials: L
authors.lastname: Racacho
authors.forename: David
authors.initials: D
authors.lastname: Ye
authors.forename: Howard
authors.initials: H
authors.lastname: Yang
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Matthew
authors.initials: M
authors.lastname: Farrer
authors.forename: G Angus
authors.initials: GA
authors.lastname: McQuibban
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D004795:Enzyme Stability / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D045726:Metalloproteases / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology*; D011494:Protein Kinases / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D045726:Metalloproteases; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C485223:PARL protein, human