Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Abstract

Urate is the end product of purine metabolism in humans, owing to the evolutionary disruption of the gene encoding urate oxidase (UOx). Elevated urate can cause gout and urolithiasis and is associated with cardiovascular and other diseases. However, urate also possesses antioxidant and neuroprotective properties. Recent convergence of epidemiological and clinical data has identified urate as a predictor of both reduced risk and favorable progression of Parkinson's disease (PD). In rodents, functional UOx catalyzes urate oxidation to allantoin. We found that UOx KO mice with a constitutive mutation of the gene have increased concentrations of brain urate. By contrast, UOx transgenic (Tg) mice overexpressing the enzyme have reduced brain urate concentrations. Effects of the complementary UOx manipulations were assessed in a mouse intrastriatal 6-hydroxydopamine (6-OHDA) model of hemiparkinsonism. UOx KO mice exhibit attenuated toxic effects of 6-OHDA on nigral dopaminergic cell counts, striatal dopamine content, and rotational behavior. Conversely, Tg overexpression of UOx exacerbates these morphological, neurochemical, and functional lesions of the dopaminergic nigrostriatal pathway. Together our data support a neuroprotective role of endogenous urate in dopaminergic neurons and strengthen the rationale for developing urate-elevating strategies as potential disease-modifying therapy for PD.U rate, the anionic component of uric acid, predominates at physiological pH. As an apparent consequence of mutations in the urate oxidase (UOx) gene during primate evolution, urate constitutes the enzymatic end product of purine metabolism in humans (1). There remains controversy over how the loss of UOx activity and the resultant high urate concentrations in hominoids may have been beneficial and whether it still is. On one hand, urate is considered a pathogenic factor in gout, urolithiasis, and nephropathy, and hyperuricemia is associated with other medical conditions, such as hypertension, cardiovascular disease, and metabolic syndrome (2). On the other hand, the loss of UOx activity through multiple independent mutations in hominoids presumably conferred evolutionary advantages. Urate possesses potent antioxidant properties. High urate levels may have provided an antioxidant defense against aging and cancer, thereby contributing to a prolonged hominoid life span (3). In addition, increased urate may mediate blood pressure homeostasis in low-salt environments. Furthermore, higher urate has been suggested to enhance human intelligence or motivational behaviors or promote neuronal integrity and function (4).Recently a series of population and clinical epidemiology studies have lent support to a potential neuroprotective effect of urate (5,6). These studies demonstrated a robust inverse link between urate levels and both the risk and clinical progression of Parkinson's disease (PD), one of the most common neurodegenerative diseases. Given the putative role of oxidative stress in the pathogenesis of PD (7), these studies have i...

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

“…In vivo, genetic manipulation of urate oxidase and resulting increased concentrations of urate in the CNS led to improved phenotype and histopathologic findings in PD mouse models [35,49]. These data substantiate earlier findings in PC12 cells, in which urate blocked cell death and oxidative damage induced by either dopamine [50] or 6-hydroxydopamine [51].…”

“…Neuroprotective [35] Neuroprotective in SCI, brain ischemia/stroke, MS [38][39][40][41] Clinical trials SURE-PD (phase II trial) [10] URICO-ICTUS (phase IIb/III trial in stroke) [42,43] PD = Parkinson's disease; ALS = amyotrophic lateral sclerosis; AD = Alzheimer's disease; HD = Huntington's disease; MSA = multiple system atrophy; MCI = mild cognitive impairment; SCI = spinal cord injury; MS = multiple sclerosis …”

High Expression Levels of NADPH Oxidase 3 in the Cerebrum of Ten-Week-Old Stroke-Prone Spontaneously Hypertensive Rats

“…12) In the present study, we found that XO mRNA levels were significantly lower in SHRSP (Table 4). Reductions in urate content due to a decrease in XO mRNA level may also be partly involved in the high levels of oxidative stress observed in the SHRSP cerebrum.…”

Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis

“…Urate, the end‐product of human purine metabolism, is an endogenous antioxidant10, 11 and proposed neuroprotectant12, 13, 14, 15 and its levels may be increased by edaravone treatment 6, 16. High urate levels correlate with improved survival in ALS epidemiologic studies17, 18, 19, 20, 21, 22, 23 and with favorable outcomes in other neurodegenerative diseases, most notably Parkinson's disease (PD) 24, 25, 26.…”

“…High urate levels correlate with improved survival in ALS epidemiologic studies17, 18, 19, 20, 21, 22, 23 and with favorable outcomes in other neurodegenerative diseases, most notably Parkinson's disease (PD) 24, 25, 26. Further, urate is neuroprotective in several models of neurodegeneration 12, 27, 28, 29, 30, 31, 32…”