The protein DJ-1 has been implicated to play a role in neurodegenerative diseases, such as multiple system atrophy and Parkinson's disease (PD). Mutations in the DJ-1 gene have been linked to an autosomal recessive early onset form of parkinsonism and presumably result in diminished or completely attenuated DJ-1 activity. A growing body of evidence suggests that DJ-1 may be involved in protecting neurons from mitochondrial dysfunction and oxidative damage. This proposal builds directly on the recent Michael J. Fox Foundation Transgenic Initiative, which resulted in the generation of transgenic mice with reduced and null DJ-1 expression. The purpose of this proposal is two-fold: 1) to characterize any pathology which may develop in heterozygous and homozygous null expressors, with specific emphasis on the nigral dopaminergic neurons and 2) to determine whether the lack of DJ-1 renders the nigrostriatal pathway more sensitive to injury elicited through neurotoxicant exposure or proteasomal impairment. The proposed studies will determine whether the null DJ-1 transgenics provide a relevant new model for studying the development of PD-like pathology and for assessing the role of DJ-1, specifically, in the events involved in nigral dopaminergic cell degeneration.