Protection by Purines in Toxin Models of Parkinson's Disease
Abstract
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2013
- Accession Number
- ADA602446
Entities
People
- Michael A Schwarzschild
Organizations
- Massachusetts General Hospital