title: PINK1 defect causes mitochondrial dysfunction, proteasomal deficit and alpha-synuclein aggregation in cell culture models of Parkinson's disease.
abstract: Mutations in PTEN induced kinase 1 (PINK1), a mitochondrial Ser/Thr kinase, cause an autosomal recessive form of Parkinson's disease (PD), PARK6. Here, we report that PINK1 exists as a dimer in mitochondrial protein complexes that co-migrate with respiratory chain complexes in sucrose gradients. PARK6 related mutations do not affect this dimerization and its associated complexes. Using in vitro cell culture systems, we found that mutant PINK1 or PINK1 knock-down caused deficits in mitochondrial respiration and ATP synthesis. Furthermore, proteasome function is impaired with a loss of PINK1. Importantly, these deficits are accompanied by increased alpha-synclein aggregation. Our results indicate that it will be important to delineate the relationship between mitochondrial functional deficits, proteasome dysfunction and alpha-synclein aggregation.
authors.affiliation: Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Liu
authors.forename: Cristofol
authors.initials: C
authors.lastname: Vives-Bauza
authors.forename: Rebeca
authors.initials: R
authors.lastname: Acín-Peréz-
authors.forename: Ai
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Tan
authors.forename: Yanping
authors.initials: Y
authors.lastname: Li
authors.forename: Jordi
authors.initials: J
authors.lastname: Magrané
authors.forename: Mihaela A
authors.initials: MA
authors.lastname: Stavarache
authors.forename: Sebastian
authors.initials: S
authors.lastname: Shaffer
authors.forename: Simon
authors.initials: S
authors.lastname: Chang
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kaplitt
authors.forename: Xin-Yun
authors.initials: XY
authors.lastname: Huang
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
authors.forename: Chenjian
authors.initials: C
authors.lastname: Li
mesh_terms: D006801:Humans; D008928:Mitochondria / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010085:Oxidative Phosphorylation; D010300:Parkinson Disease; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency*; D011494:Protein Kinases / Q000235:genetics*; D051844:alpha-Synuclein / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D024101:Mitochondrial Proteins; D046988:Proteasome Endopeptidase Complex; D011494:Protein Kinases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase