Parkin stabilizes PINK1 through direct interaction.
Parkinson disease (PD) is the most common movement disorder and is characterized by dopaminergic dysfunction. The majority of PD cases are sporadic; however, the discovery of genes linked to rare familial forms of the disease has provided crucial insight into the molecular mechanisms of disease pathogenesis. Multiple genes mediating familial forms of Parkinson's disease (PD) have been identified, such as parkin (PARK2) and phosphatase and tensin homologue deleted on chromosome ten (PTEN)-induced putative kinase 1: PINK1 (PARK6). Here, we showed that Parkin directly interacts with PINK1, but did not bind to pathogenic PINK1 mutants. Parkin, but not its pathogenic mutants, stabilizes PINK1 by interfering with its degradation via the ubiquitin-mediated proteasomal pathway. In addition, the interaction between Parkin and PINK1 resulted in reciprocal reduction of their solubility. Our results indicate that Parkin regulates PINK1 stabilization via direct interaction with PINK1, and operates through a common pathway with PINK1 in the pathogenesis of early-onset PD.
Research Institute for Diseases of Old Age, Juntendo University School of Medicine, Hongo, Bunkyo, Tokyo, Japan.
Kahori
K
Shiba
Takeo
T
Arai
Shigeto
S
Sato
Shin-ichiro
S
Kubo
Yusuke
Y
Ohba
Yoshikuni
Y
Mizuno
Nobutaka
N
Hattori
D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism*; D055550:Protein Stability; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein