JNK activation by tetrahydrobiopterin: implication for Parkinson's disease.
Parkinson's disease (PD) is a progressive neurologic disease associated with selective degeneration of dopaminergic neurons in the substantia nigra. Despite extensive studies to understand the underlying cause of dopaminergic degeneration, the pathologic factors leading to this neuronal loss in PD remain obscure. We have observed previously that tetrahydrobiopterin (BH4) exerts selective toxicity and oxidative stress on dopaminergic cells, suggesting that BH4 might participate endogenously in dopaminergic neurodegeneration in PD. We investigated signaling events leading to BH4 toxicity in dopaminergic CATH.a cells. We show that c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein kinase (MAPK), is phosphorylated significantly by BH4 exposure. BH4 also leads to c-Jun phosphorylation and an increase in c-Jun protein level. The JNK inhibitor SP600125 protects cells against BH4 toxicity and inhibits cytochrome c release and apoptotic nuclear condensation induced by BH4. These data indicate that activation of the JNK pathway is important in mediating BH4-induced dopaminergic cell death.
Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
Hyun Jin
HJ
Choi
So Yeon
SY
Lee
Yuri
Y
Cho
Onyou
O
Hwang
D000818:Animals; D000975:Antioxidants / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000633:toxicity*; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D009498:Neurotoxins / Q000633:toxicity; D010300:Parkinson Disease / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D009498:Neurotoxins; D001708:Biopterins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C003402:sapropterin; D004298:Dopamine