Impairment of Oxidative Stress-Induced Heme Oxygenase-1 Expression by the Defect of Parkinson-Related Gene of Pink1
Resource
JOURNAL OF NEUROCHEMISTRY v.117 n.4 pp.643-653
Journal
JOURNAL OF NEUROCHEMISTRY
Journal Volume
v.117
Journal Issue
n.4
Pages
643-653
Date Issued
2011
Date
2011
Author(s)
CHIEN, WEI-LIN
LEE, TZENG-RUEI
HUNG, SHIH-YA
KANG, KAI-HSIANG
LEE, MING-JEN
FU, WEN-MEI
Abstract
P>Parkinsons 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 H2O2 or 1- methyl-4-phenylpyridinium MPP+ treatment. The HO-1 induction in response to H2O2 and MPP+ treatment was impaired by the expression of recombinant PINK1 G309D mutant. PINK1 G309D mutation increased the apoptosis of SH-SY5Y cells following H2O2 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 H2O2 treatment was inhibited by the expression of recombinant PINK1 G309D mutant. The H2O2- 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.
Subjects
heme oxygenase-1
Parkinsons disease
PTEN-induced putative kinase 1
tumor necrosis factor receptor-associated protein-1