Impairment of oxidative stress-induced heme oxygenase-1 expression by the defect of Parkinson-related gene of PINK1

J Neurochem. 2011 May;117(4):643-53. doi: 10.1111/j.1471-4159.2011.07229.x. Epub 2011 Apr 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenylpyridinium / toxicity
  • Adenoviridae / genetics
  • Benzimidazoles
  • Blotting, Western
  • Cell Line
  • Cell Survival / drug effects
  • Cloning, Molecular
  • Coloring Agents
  • Dopamine / metabolism
  • Fluorescent Antibody Technique
  • Fluorescent Dyes
  • Gene Expression Regulation
  • Genetic Vectors
  • HSP90 Heat-Shock Proteins / biosynthesis
  • HSP90 Heat-Shock Proteins / genetics
  • Heme Oxygenase-1 / biosynthesis*
  • Humans
  • L-Lactate Dehydrogenase / metabolism
  • Mutation
  • Oxidative Stress / physiology*
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / genetics*
  • Parkinson Disease, Secondary / metabolism*
  • Protein Kinases / biosynthesis
  • Protein Kinases / genetics*
  • RNA / biosynthesis
  • RNA / isolation & purification
  • Reactive Oxygen Species
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tetrazolium Salts
  • Thiazoles


  • Benzimidazoles
  • Coloring Agents
  • Fluorescent Dyes
  • HSP90 Heat-Shock Proteins
  • Reactive Oxygen Species
  • TRAP1 protein, human
  • Tetrazolium Salts
  • Thiazoles
  • RNA
  • L-Lactate Dehydrogenase
  • Heme Oxygenase-1
  • Protein Kinases
  • PTEN-induced putative kinase
  • thiazolyl blue
  • bisbenzimide ethoxide trihydrochloride
  • 1-Methyl-4-phenylpyridinium
  • Dopamine