Developing Tools to Understand an Alternative Fate of Urate in Neurodegenerative Diseases

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ABSTRACT Urate is the salt form of uric acid predominantly found in the circulation and is considered a major plasma antioxidant. Low levels of serum urate at diagnosis are associated with accelerated disease progression and lower patient survival in several neurodegenerative diseases. For example, urate levels are lower in Parkinson’s Disease (PD) patients and this correlates with loss of the striatal dopamine transporter and an advanced clinical progression in motor deficits. Similarly, several studies have suggested that urate levels may offer value as a prognostic biomarker for Amyotrophic Lateral Sclerosis (ALS) progression, yet it remains unclear why low uric acid reflects poor survival. Recently, a large effort to increase urate levels (inosine supplementation) in PD patients offered no clinical benefit or improvement in patient outcomes. Why does the supplementation of a major plasma antioxidant confer no benefit to patients in diseases where oxidative stress is known to be present? Our expertise in studying the chemical modification of proteins by metabolites led us to consider an alternative fate of urate when oxidative stress may overwhelm the regeneration of urate antioxidant capacity. We hypothesize that low plasma urate instead reflects increased oxidation of urate to generate reactive urate radicals that can chemically modify protein lysine residues, altering protein structure or function, a process known as protein uratylation. The balance between urate antioxidant benefit, and urate oxidation to damaging radicals, may uniquely depend on the location and nature of the oxidative stress. In this R03 we are embarking on exploratory studies to better understand why urate therapy may not have been as successful as anticipated. Our goal is to generate and validate new tools that will assist movement disorders researchers in the future in testing the relevance of protein uratylation across a range of preclinical models and human biospecimens.