Urate and Its Transgenic Depletion Modulate Neuronal Vulnerability in a Cellular Model of Parkinson's Disease

Cipriani, Sara; Desjardins, Cody A.; Burdett, Thomas C.; Xu, Yiling; Xu, Kui; Schwarzschild, Michael A.

doi:10.1371/journal.pone.0037331

Cited by 61 publications

(52 citation statements)

References 53 publications

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“…The exacerbated neurotoxicity of 6-OHDA on the nigrostriatal dopaminergic pathway in UOx Tg mice entails greater DA depletion, more extensive neuron loss, and exacerbated asymmetry of movement. These findings in vivo are consistent with our recent report that this UOx transgene exacerbates dopaminergic neuron degeneration in a cellular model of PD (26).…”

Section: Discussionsupporting

confidence: 93%

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Chen

Burdett

Desjardins

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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110

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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...

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Section: Discussionsupporting

confidence: 93%

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Chen

Burdett

Desjardins

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

110

121

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“…In vitro, urate attenuated the loss of dopaminergic neurons in neuron-enriched cultures induced by diverse neurotoxicants. 23,24 Neuroprotective effects of urate were also supported by a series of human PD studies, as listed in table e-1. In a double-blind, placebo-controlled, randomized trial of urate precursor inosine in 75 patients with early PD, we observed nonfutility of inosine treatment for slowing disability.…”

Section: Resultsmentioning

confidence: 72%

Prospective study of plasma urate and risk of Parkinson disease in men and women

et al. 2016

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Objective: To examine whether higher plasma urate concentrations are associated with a lower risk of developing Parkinson disease (PD) and whether there is a sex difference in the potential urate-PD relationship. Methods:We conducted a nested case-control study based on 90,214 participants of 3 ongoing US cohorts. We identified 388 new PD cases (202 men and 186 women) since blood collection, which were then matched to 1,267 controls. PD cases were confirmed by medical record review. Conditional logistic regression estimated relative risks (RRs) and 95% confidence intervals (95% CIs), after adjustment for age, smoking, caffeine intake, plasma concentrations of cholesterol and ferritin, and other covariates. We also conducted a meta-analysis to combine our study with 3 previously published prospective studies on urate and PD risk. Results:In the present nested case-control study, the multivariate-adjusted RRs of PD comparing extreme quartiles of urate were 0.63 (95% CI 0.35, 1.10; p trend 5 0.049) in men and 1.04 (95% CI 0.61, 1.78; p trend 5 0.44) in women (p heterogeneity 5 0.001). In the meta-analysis, the pooled RRs comparing 2 extreme quartiles of urate were 0.63 (95% CI 0.42, 0.95) in men and 0.89 (95% CI 0.57, 1.40) in women. Conclusion:We observed that men, but not women, with higher urate concentrations had a lower future risk of developing PD, suggesting that urate could be protective against PD risk or could slow disease progression during the preclinical stage of disease. Urate is a potent antioxidant and contributes to approximately 60% of the free radical scavenging activity in human serum.1,2 Serum urate concentrations in humans and apes are many-fold higher than those in other mammals as a consequence of evolutionary urate oxidase gene mutations.1 Results from in vitro and in vivo experimental studies suggest that urate could be a potential neuroprotective agent via its capacity to modify the cerebral damage induced by reactive nitrogen and oxidative species.2,3 In most, 4-8 but not all, 9 prospective observational studies in humans, higher concentrations of plasma urate were associated with a lower risk of developing Parkinson disease (PD). Further, patients with PD with higher urate levels have been found to have a slower disease progression relative to those with lower urate concentrations. 10,11 However, significant associations of higher urate levels with lower PD risk and slower progression were observed only in men. [4][5][6][7][8][9] Studies relating blood urate levels to PD risk were limited by their small sample sizes (PD case number , 160 in all studies) and underrepresentation of women. Therefore, it remains unclear whether this sex difference reflects a true difference in underlying biology or is due to lack of statistical power because women generally have lower urate concentration and lower PD incidence compared with men. Further, only one previous study 7 controlled for plasma ferritin and cholesterol levels, which have been found to be

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“…In vitro, in PD models, urate prevents spontaneous degeneration of cultured nigral neurons, as well as dopaminergic cell death induced by oxidative and mitochondrial toxins [34,36]. 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].…”

Section: Urate Is Neuroprotective In Several Preclinical Models Of Nementioning

confidence: 99%

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

Paganoni

Schwarzschild

2017

Neurotherapeutics

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Urate is a naturally occurring antioxidant whose levels are associated with reduced risk of developing Parkinson's disease (PD) and Alzheimer's disease. Urate levels are also associated with favorable progression in PD, amyotrophic lateral sclerosis, Huntington's disease, and multisystem atrophy. These epidemiological data are consistent with laboratory studies showing that urate exhibits neuroprotective effects by virtue of its antioxidant properties in several preclinical models. This body of evidence supports the hypothesis that urate may represent a shared pathophysiologic mechanism across neurodegenerative diseases. Most importantly, beyond its role as a molecular predictor of disease risk and progression, urate may constitute a novel therapeutic target. Indeed, clinical trials of urate elevation in PD and amyotrophic lateral sclerosis are testing the impact of raising peripheral urate levels on disease outcomes. These studies will contribute to unraveling the neuroprotective potential of urate in human pathology. In parallel, preclinical experiments are deepening our understanding of the molecular pathways that underpin urate's activities. Altogether, these efforts will bring about new insights into the translational potential of urate, its determinants, and its targets and their relevance to neurodegeneration.

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Urate and Its Transgenic Depletion Modulate Neuronal Vulnerability in a Cellular Model of Parkinson's Disease

Cited by 61 publications

References 53 publications

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Prospective study of plasma urate and risk of Parkinson disease in men and women

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

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