Parkinson's Disease (PD) is one of the most frequent neurodegenerative disorders. It is an extrapyramidal movement disorder characterized by the progressive loss of dopamine (DA) neurons in substantia nigra (SN). Recent progress in linkage studies on patients with familial PD has led to the identification of several genes implicated in this disease. One of these genes, parkin, is linked to Autosomal Recessive-Juvenile Parkinson's Disease (AR-JP). Deletions, truncations, and point mutations of parkin in AR-JP patients are correlated with their PD symptoms. However, it is not clear whether the loss of function for this gene directly causes PD, and if so, how does it occur? We propose to answer these questions by generating the parkin knockout mice. They will be used to study whether the deletion of parkin directly leads to selective loss of nigral DA neurons, and PD-like symptoms in mice. Since parkin is widely expressed in many tissues, and yet the progressive cell death is restricted to DA neurons in SN, we hypothesize that parkin may interact with specific proteins in these neurons to sustain their survival. To test this hypothesis, we propose to identify proteins that interact with parkin by using the yeast two-hybrid system. Once these proteins are identified, we will investigate their roles, in association with parkin, in the survival of nigral DA neurons. The specific goal of this project is to understand the in vivo function of parkin and its role in the etiology of AR-JP. As AR-JP and the sporadic form of PD share many similar clinical symptoms and pathological hallmarks (e.g. death of nigral DA neurons), knowledge gained from the study of parkin may shed some light on the potentially common mechanism for PD. It is our long-term objective to use this mouse genetic model to elucidate the molecular and cellular processes that lead to the progressive and selective death of nigral dopaminergic neurons and locomotor dysfunction in PD. This animal model would also be a valuable tool for the development of more effective therapeutic strategies for PD patients.
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