The development of Parkinson's disease is accompanied by concurrent activation of caspase-3 and apoptosis of dopaminergic neurons of human patients and rodent models. The role of caspase-3, a final executioner of apoptosis, in the pathogenesis of Parkinson's disease, however, remains to be determined. Here, we show that gene disruption of caspase-3 protects mice from 1-methyle-4-phenyl-1,2,3,6-tetrahmydropyridine (MPTP)-induced Parkinsonian syndrome, as reflected by reversal of MPTP-induced bradykinesia and decreased tyrosine hydroxylase expression in the nigra-striatum. MPTP treatment resulted in increased caspase-3 activation and apoptosis in the substantia nigra of wild-type mice at 24 h after the inception of MPTP treatment, as compared with vehicle-treated control animals. Gene disruption of caspase-3 prevented MPTP-induced apoptosis in the substantia nigra. At 7 days after MPTP treatment, tyrosine hydroxylase expression was suppressed and infiltration of activated microglia and astrocytes was markedly increased in the nigra-striatum of wild-type mice. All of these alterations following MPTP treatment were blocked by disruption of caspase-3 in mice. These results clearly indicate that caspase-3 activation is required for the development of MPTP-induced Parkinson's disease in mice. These findings suggest that activation of caspase-3-mediated apoptosis of dopaminergic neurons in the early stage may play an important role in the pathogenesis of Parkinson's disease. (C) 2010 Elsevier Inc. All rights reserved.