PINK1 defect causes mitochondrial dysfunction, proteasomal deficit and alpha-synuclein aggregation in cell culture models of Parkinson's disease.
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.
Liu
Wencheng
W
Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, New York, USA.
Vives-Bauza
Cristofol
C
Acín-Peréz-
Rebeca
R
Yamamoto
Ai
A
Tan
Yingcai
Y
Li
Yanping
Y
Magrané
Jordi
J
Stavarache
Mihaela A
MA
Shaffer
Sebastian
S
Chang
Simon
S
Kaplitt
Michael G
MG
Huang
Xin-Yun
XY
Beal
M Flint
MF
Manfredi
Giovanni
G
Li
Chenjian
C
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
D024101:Mitochondrial Proteins; D046988:Proteasome Endopeptidase Complex; D011494:Protein Kinases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase