Protection by Purines in Toxin Models of Parkinson's Disease
Final rept. 17 Jan 2011-14 Jun 2013
MASSACHUSETTS GENERAL HOSPITAL BOSTON
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In Year 2 of the project substantial progress has been made toward our original Specific Aims SAs and broader central goal of elucidating the neuroprotective potential and mechanisms of purines implicated in the neurodegeneration of Parkinson s disease PD. Major published findings during Year 2 included our demonstrations that -synuclein toxicity in a mouse model of PD depends upon caffeine s putative molecular target, the adenosine A2A receptor SA1 that raising or lowering endogenous urate through knockout KO of the urate oxidase UOx gene or its transgenic overexpression attenuates or exacerbates, respectively, toxininduced dopaminergic neuron degeneration in mouse models of PD SA2 and that urate confers protection against oxidative toxins in cellular models of PD in a strikingly astrocyte-dependent manner SA3. We also published methodological and collaborative progress in support of all three SAs. Recently we have obtained preliminary data identifying released glutathione as a likely candidate for the astrocytic protective factor. In addition in year 2 we have begun to characterize a conditional UOx KO to obviate developmental confounds of the initially reported constitutive UOx KO. Together our findings strengthen the rationale for pursuing purine targets as candidate neuroprotective strategies for PD, and have epidemiological and military as well as translational significance.
- Medicine and Medical Research