title: Impairment of oxidative stress-induced heme oxygenase-1 expression by the defect of Parkinson-related gene of PINK1.
abstract: Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Mutation in the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) gene causes an autosomal recessive form of PD. However, the etiology related to PINK1 is still not clear. Here, we examined the effect of PINK1 on heme oxygenase (HO)-1 induction in SH-SY5Y neuronal cells following H(2)O(2) or 1-methyl-4-phenylpyridinium (MPP(+)) treatment. The HO-1 induction in response to H(2)O(2) and MPP(+) treatment was impaired by the expression of recombinant PINK1 G309D mutant. PINK1 G309D mutation increased the apoptosis of SH-SY5Y cells following H(2)O(2) treatment and cell survival was rescued by the over-expression of HO-1 using adenovirus (Ad) infection. In addition, knockdown of tumor necrosis factor receptor-associated protein-1 (TRAP1), which is the substrate of PINK1 kinase, in SH-SY5Y cells also inhibited the expression of HO-1 in response to oxidative stress. The up-regulation of TRAP1 expression following H(2)O(2) treatment was inhibited by the expression of recombinant PINK1 G309D mutant. The H(2)O(2)-induced HO-1 induction was Akt- and ERK-dependent. The phosphorylation of ERK and Akt but not p38 was inhibited in cells expressing the PINK1 G309D mutant and knockdown of TRAP1. These results indicate a novel pathway by which the defect of PINK1 inhibits the oxidative stress-induced HO-1 production. Impairment of HO-1 production following oxidative stress may accelerate the dopaminergic neurodegeneration in Parkinson patients with PINK1 defect.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University Hospital, 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: Ming-Jen
authors.initials: MJ
authors.lastname: Lee
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Fu
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000256:Adenoviridae / Q000235:genetics; D001562:Benzimidazoles; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003001:Cloning, Molecular; D004396:Coloring Agents; D004298:Dopamine / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress / Q000502:physiology*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts; D013844:Thiazoles; D000099202:PTEN-Induced Putative Kinase
chemical_list: D015655:1-Methyl-4-phenylpyridinium; D001562:Benzimidazoles; D004396:Coloring Agents; D004298:Dopamine; D005456:Fluorescent Dyes; D018841:HSP90 Heat-Shock Proteins; D051547:Heme Oxygenase-1; D007770:L-Lactate Dehydrogenase; D011494:Protein Kinases; D012313:RNA; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; D000099202:PTEN-Induced Putative Kinase; C092306:TRAP1 protein, human; C022616:thiazolyl blue; C017807:bisbenzimide ethoxide trihydrochloride