Parkinson's disease (PD) is a frequent cause of neurodegeneration, disability and premature mortality in older adults. Loss of dopaminergic neurons in the substantia nigra is the primary neuropathological hallmark of PD. There are currently no treatments proven to slow down the progressive nigral cell loss in PD, which causes increasing severity of the clinical symptoms. The recent linking of human mutations in genes such as Parkin, DJ-1, and PINK1 to recessively inherited forms of PD provides new opportunities to discover pathogenic mechanisms and to develop and test neuroprotective therapies in animal models with nigral cell loss based on mechanisms physiologically relevant to human parkinsonism. We have pursued this strategy for over a decade using knockout (KO) mice. For unknown reasons, without further insult, Parkin KO, DJ-1 KO and PINK1 KO mice do not reproduce the nigral cell loss that occurs in humans bearing loss-of-function mutations in these genes. The lack of nigral cell loss precludes using nigral cell loss as an outcome measure to directly test potential pathogenic mechanisms and neuroprotective strategies in Parkin KO, DJ-1 KO or PINK1 KO mice. Recently developed DJ-1 KO rats show age-dependent nigral cell loss with a full complement of dopamine neurons at ages 4 months and 6 months but greater than 50% loss by age 8 months. The age-dependent nigral neuron loss in DJ-1 KO rats makes it possible for the first time to test candidate pathogenic mechanisms directly in a mammalian brain that reproduces this central neuropathological feature of PD. We propose to use DJ-1 KO rats to achieve the following specific aims based on previous in vitro studies of DJ-1 function and pathogenic mechanisms of DJ-1 mutations: 1) To determine whether DJ-1 expression in neurons, astrocytes or both is required to prevent age-dependent loss of nigral dopamine neurons in rats and 2) To determine whether DJ-1 cysteine 106 is required for DJ-1 in vivo to prevent nigral cell loss. We expect to contribute a systematic characterization of DJ-1 KO rats as an apt test bed for therapeutic development by testing the principal hypothesis that cysteine 106 is required for DJ-1 to prevent nigral cell loss in DJ-1 KO rats and the second main hypothesis that DJ-1 expression in astrocytes is required to prevent nigral cell loss in DJ-1 KO rats. The use of this novel rat model of nigral cell loss is innovative and the proposal will significantly impact the understanding of PD by shifting emphasis to disease mechanisms present in PD brain tissue selected for their strong therapeutic potential. We expect that our findings will be broadly applicable to the development of neuroprotective therapies for familial and sporadic PD as well as other neurodegenerative diseases.