title: Increase of oxidative stress by a novel PINK1 mutation, P209A.
abstract: Mutation in the human PTEN-induced protein kinase 1 (PINK1) gene is responsible for the second most common form of recessive Parkinson disease (PD). We have identified a single heterozygous PINK1 mutation, P209A, from a cohort of 68 patients with early onset PD. From age 31, this patient developed an asymmetric bradykinesia with rigidity that was L-DOPA responsive. An [(18)F]-fluorodopa PET scan showed reduced DOPA uptake in the bilateral basal ganglia. The H2O2-induced cell death, ROS production, and caspase-3 activation in SH-SY5Y cells were enhanced by the transfection of the PINK1 P209A mutant. The heme oxygenase-1 (HO-1) induction in response to H2O2 and MPP(+) treatment was impaired by the overexpression of the PINK1 P209A mutant. In addition, SOD2 induction after TNFα treatment was also inhibited by the PINK1 P209A mutation. Akt and ERK are involved in HO-1 induction after oxidative stress. The phosphorylation of Akt and ERK after exposure to H2O2 or MPP(+) was also inhibited in PINK1 P209A mutant cells compared with empty-vector-transfected cells. These results indicate a novel pathway by which the P209A defect in the PINK1 kinase domain inhibits oxidative stress-induced HO-1 and SOD2 induction, which may accelerate the neurodegeneration in PD with PINK1 defect.
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Chien
authors.forename: Tzeng-Ruei
authors.initials: TR
authors.lastname: Lee
authors.forename: Shih-Ya
authors.initials: SY
authors.lastname: Hung
authors.forename: Kai-Hsiang
authors.initials: KH
authors.lastname: Kang
authors.forename: Ruey-Meei
authors.initials: RM
authors.lastname: Wu
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Lee
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Fu
mesh_terms: D017668:Age of Onset; D002460:Cell Line; D005260:Female; D020022:Genetic Predisposition to Disease; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007980:Levodopa / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics*; D013482:Superoxide Dismutase / Q000378:metabolism; D000099156:Superoxide Dismutase 2; D000099202:PTEN-Induced Putative Kinase
chemical_list: D051547:Heme Oxygenase-1; D007980:Levodopa; D011494:Protein Kinases; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; D000099202:PTEN-Induced Putative Kinase; C496541:HMOX1 protein, human