The identification of genetic mutations responsible for familial forms of Parkinson's disease (PD) offers the potential to glean insight into the mechanisms underlying the sporadic form of the disease. Currentmouse models based on deletions or mutations in two such genes, parkin and alpha-synucein, do not exhibit dopaminergic neuron degeneration. However, close scrutiny of two of these models within our Center, has revealed behavioral (Project 1), neurochemical (Project 2) and electrophysiological (Project 3) deficits, which likely model early stages of the progressive human disease process, prior to neuronal degeneration. The goal of the Center is to build on this multidisciplinary approach to determine the time-course of progression of cell dysfunction in multiple genetic models of PD in order to identify common deficits, since these are most likely to be of relevance to sporadic PD. By elucidating the mechanisms responsible for these deficits we hope to uncover therapeutic targets for preventing disease progression, prior to the loss of significant numbers of dopamine (DA) neurons. This project builds upon our observation that striatal extracellular DA levels are elevated in parkin exon 3 KO and alpha-synuclein over-expressing mice, a finding of significance given the potential of DA to promote oxidative stress and, ultimately, cell death. We will determine: 1) if this observation generalizes to parkin exon 2 KO mice, to mice, produced by the Mouse Genetics Core, expressing a parkin mutation shown to cause DA cell death in flies, and to other models of alpha-synuclein over-expression 2) whether transmitter systems other than DA are also disrupted, given the recognized importance of non-motor symptoms in PD, studied in Project 5, and modeled in Project 1;3) if the increased extracellular DA results from dysregulation of vesicular release, reuptake, reverse transport or metabolism; 4) whether, given the association of parkin and synuclein with components of synaptic vesicles (Project 4), our observations can be explained by disruption of synaptic vesicle cycling.
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