Rotenone induces apoptosis via activation of bad in human dopaminergic SH-SY5Y cells.

Chronic complex I inhibition caused by rotenone induces features of Parkinson's disease in rats, including selective nigrostriatal dopaminergic degeneration and Lewy bodies with alpha-synuclein-positive inclusions. To determine the mechanisms underlying rotenone-induced neuronal death, we used an in vitro model of human dopaminergic SH-SY5Y cells. In rotenone-induced cell death, rotenone induced ...
Bad dephosphorylation without changing the amount of Bad proteins. Rotenone also increased the amount of alpha-synuclein in cells showing morphological changes in response to rotenone. Because Bad and alpha-synuclein are known to bind to 14-3-3 proteins, we examined the effects of rotenone on these complexes. Whereas a decreased Bad amount bound to 14-3-3 proteins, rotenone increased alpha-synuclein binding to these proteins. Because dephosphorylation by calcineurin activates Bad, we examined the possible involvement of Bad activation in rotenone-induced apoptosis by using the calcineurin inhibitor tacrolimus (FK506). Tacrolimus suppressed two rotenone-induced actions: Bad dephosphorylation and apoptosis. Furthermore, the inhibition of caspase-9, which functions downstream from Bad, completely suppressed rotenone-induced apoptosis. Our findings demonstrate that Bad activation plays a role in rotenone-induced apoptosis of SH-SY5Y cells.
Mesh Terms:
Apoptosis, Biotransformation, Blotting, Western, Carrier Proteins, Caspase 9, Caspases, Cell Line, Cell Nucleus, DNA Fragmentation, Dopamine, Dose-Response Relationship, Drug, Electrophoresis, Agar Gel, Humans, Immunoprecipitation, Immunosuppressive Agents, Microscopy, Fluorescence, Nerve Tissue Proteins, Phosphorylation, Rotenone, Synucleins, Tacrolimus, Uncoupling Agents, alpha-Synuclein, bcl-Associated Death Protein
J. Pharmacol. Exp. Ther.
Date: Dec. 01, 2004
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