Targeting Urate: A Molecular Correlate of Both Risk and Progression in PD

Objective/Rationale:
Urate (a natural antioxidant, caffeine analog and DNA metabolite) is the first molecule linked to both the risk of typical Parkinson’s disease and its rate of progression. Higher levels of urate in the general population are associated with a reduced risk of developing Parkinson’s disease. And amongst those who have already developed the disease, higher urate levels are a predictor of a more favorable rate of disease progression. The objective of the project is to determine whether urate can serve as a neuroprotectant against brain cell degeneration in a pre-clinical model of Parkinson’s disease.
Project Description:
Is it biologically plausible that urate works to reduce brain cell loss in Parkinson’s disease? To address this question, the role of urate will be investigated in a laboratory model of Parkinson’s disease. In this pre-clinical model a pair of pesticides are twice weekly administered for six weeks leading to the degeneration of the same kind of dopamine-releasing brain cells that characteristically degenerate in Parkinson’s disease. Complementary drug and gene manipulations that alter brain levels of urate will be studied for their effects on the survival of these brain cells in the pesticide model of Parkinson’s disease. Specifically, the first set of experiments will test the effects of brainpenetrant drugs that boost or block urate production. The second set will test the effects of mouse gene modifications (mutations and insertions) that raise or lower urate levels by preventing or accelerating the normal degradation of urate.

Anticipated Outcome and Relevance to Diagnosis/Treatment of Parkinson’s Disease:
A demonstration that urate is able to protect brain cells in a model of Parkinson’s disease would:
1) support (but would not prove) the possibility that higher urate is a predictor better outcomes in Parkinson’s disease because urate is actually protecting against disease progression.
2) establish a new animal model that will help us figure out how urate might protect the brain cells that degenerate in Parkinson’s disease.
3) accelerate the development of clinical trials of potentially neuroprotective urateelevating strategies in Parkinson’s disease.