title: PINK1 and Parkin complementarily protect dopaminergic neurons in vertebrates.
abstract: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by selective dopaminergic cell loss in the substantia nigra, but its pathogenesis remains unclear. The recessively inherited familial PD genes PARK2 and PARK6 have been attributed to mutations in the Parkin and PTEN-induced kinase 1 (PINK1) genes, respectively. Recent reports suggest that PINK1 works upstream of Parkin in the same pathway to regulate mitochondrial dynamics and/or conduct autophagic clearance of damaged mitochondria. This phenomenon is preserved from Drosophila to human cell lines but has not been demonstrated in a vertebrate animal model in vivo. Here, we developed a medaka fish (Oryzias latipes) model that is deficient in Pink1 and Parkin. We found that despite the lack of a conspicuous phenotype in single mutants for Pink1 or Parkin, medaka that are deficient in both genes developed phenotypes similar to that of human PD: late-onset locomotor dysfunction, a decrease in dopamine levels and a selective degeneration of dopaminergic neurons. Further analysis also revealed defects in mitochondrial enzymatic activity as well as cell death. Consistently, PINK1 and Parkin double-deficient MEF showed a further decrease in mitochondrial membrane potential and mitochondrial complex I activity as well as apoptosis compared with single-deficient MEF. Interestingly, these mitochondrial abnormalities in Parkin-deficient MEF were compensated by exogenous PINK1, but not by disease-related mutants. These results suggest that PINK1 and Parkin work in a complementary way to protect dopaminergic neurons by maintaining mitochondrial function in vertebrates.
authors: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. hide0729@kuhp.kyoto-u.ac.jp
authors: Hideaki
authors: H
authors: Matsui
authors: Roberto
authors: R
authors: Gavinio
authors: Takeshi
authors: T
authors: Asano
authors: Norihito
authors: N
authors: Uemura
authors: Hidefumi
authors: H
authors: Ito
authors: Yoshihito
authors: Y
authors: Taniguchi
authors: Yoshito
authors: Y
authors: Kobayashi
authors: Takakuni
authors: T
authors: Maki
authors: Jie
authors: J
authors: Shen
authors: Shunichi
authors: S
authors: Takeda
authors: Kengo
authors: K
authors: Uemura
authors: Hodaka
authors: H
authors: Yamakado
authors: Ryosuke
authors: R
authors: Takahashi
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004330:Drosophila; D029941:Fish Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009990:Oryzias / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014714:Vertebrates / Q000235:genetics / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004298:Dopamine; D029941:Fish Proteins; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein