Dopamine-related and caspase-independent apoptosis in dopaminergic neurons induced by overexpression of human wild type or mutant α-synuclein

• Published in: Experimental cell research 2006-01, Vol.312 (2), p.156-170
• Main Authors: Zhou, Z.D., Yap, B.P., Gung, A.Y.T., Leong, S.M., Ang, S.T., Lim, T.M.
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenylpyridinium - toxicity; alpha-Methyltyrosine - pharmacology; alpha-Synuclein - antagonists & inhibitors; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Caspase; Caspases - metabolism; Cell Line; Cell Survival - drug effects; Cell Survival - physiology; Dopamine; Dopamine - metabolism; Doxycycline; Gene Expression Regulation; Humans; Mice; Mutation; Neurons - drug effects; Neurons - metabolism; Neurotoxins; Oxidopamine - toxicity; Parkinson's disease; α-synuclein
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2005.10.012

Human wild type (WT) and mutant α-synuclein (α-syn) genes were overexpressed using a Tet-on expression system in stably transfected dopaminergic MN9D cells. Their overexpression induced caspase-independent and dopamine-related apoptosis not rescued by general caspase inhibitor Z-VAD-FMK. While apoptosis due to overexpression of WT α-syn was completely abrogated by a specific tyrosine hydroxylase (TH) inhibitor, α-methyl- p-tyrosine (α-MT), the inhibitor only partially rescued apoptosis caused by overexpression of α-syn mutants. In addition, overexpression of mutants enhanced the toxicity of 1-methyl-4-phenylpyridinium (MPP +) and 6-hydroxyldopamine (6-OHDA) to MN9D cells, whereas overexpression of WT protected MN9D cells against MPP + toxicity, but not against 6-OHDA. We conclude that WT α-syn is beneficial to dopaminergic neurons but its overexpression in the presence of endogenous dopamine makes it a potential threat to the cells. In contrast, mutant α-syn not only caused the loss of WT protective function but also the gain-of-toxicity which becomes more serious in the presence of dopamine and neurotoxins.