PT  - JOURNAL ARTICLE
AU  - Masahiko Watabe
AU  - Toshio Nakaki
TI  - Rotenone Induces Apoptosis via Activation of Bad in Human Dopaminergic SH-SY5Y Cells
AID  - 10.1124/jpet.104.071381
DP  - 2004 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 948--953
VI  - 311
IP  - 3
4099  - http://jpet.aspetjournals.org/content/311/3/948.short
4100  - http://jpet.aspetjournals.org/content/311/3/948.full
SO  - J Pharmacol Exp Ther2004 Dec 01; 311
AB  - Chronic complex I inhibition caused by rotenone induces features of Parkinson's disease in rats, including selective nigrostriatal dopaminergic degeneration and Lewy bodies with α-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 α-synuclein in cells showing morphological changes in response to rotenone. Because Bad and α-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 α-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. The American Society for Pharmacology and Experimental Therapeutics