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CELLULAR AND MOLECULAR

Rotenone Induces Apoptosis via Activation of Bad in Human Dopaminergic SH-SY5Y Cells

Department of Pharmacology, Teikyo University School of Medicine, Tokyo, Japan

Chronic complex I inhibition caused by rotenone induces features of Parkinson's disease in rats, including selective nigrostriatal dopaminergic degeneration and Lewy bodies with -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 -synuclein in cells showing morphological changes in response to rotenone. Because Bad and -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 -synuclein binding to these proteins. Beccause 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.

Address correspondence to: Dr. Toshio Nakaki, Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi Ward, Tokyo 173-8605, Japan. E-mail: nakaki{at}med.teikyo-u.ac.jp

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