Dopamine-related and caspase-independent apoptosis in dopaminergic neurons induced by overexpression of human wild type or mutant alpha-synuclein.
Human wild type (WT) and mutant alpha-synuclein (alpha-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 alpha-syn was completely abrogated by a specific tyrosine hydroxylase (TH) inhibitor, alpha-methyl-p-tyrosine (alpha-MT), the inhibitor only partially rescued apoptosis caused by overexpression of alpha-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 alpha-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 alpha-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.
Zhou
Z D
ZD
Department of Biological Science, National University of Singapore, 14 Science Drive 4, 117543, Singapore.
Yap
B P
BP
Gung
A Y T
AY
Leong
S M
SM
Ang
S T
ST
Lim
T M
TM
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D019805:alpha-Methyltyrosine / Q000494:pharmacology; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
C497604:SNCA protein, human; D051844:alpha-Synuclein; D019805:alpha-Methyltyrosine; D016627:Oxidopamine; D020169:Caspases; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine