Uric acid is reduced in the substantia nigra in parkinson's disease: Effect on dopamine oxidation

Church, William H.; Ward, Velma L.

doi:10.1016/0361-9230(94)90285-2

Cited by 142 publications

(116 citation statements)

References 51 publications

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“…Metabolomic analysis was also applied to plasma samples from PD patients with or without the LRRK2 G2019S mutation, along with healthy controls (101). The results showed that the metabolome pattern was clearly segregated among different groups and that uric acid levels were significantly reduced both in sporadic and LRRK2-carrying PD patients (101), which was previously reported using postmortem substantia nigra tissue samples from both PD patients and controls (102). These results raise the promising possibility that, to diagnose PD and to measure effectiveness of treatment, patient blood can be utilized.…”

Section: Normal and Pathological Features Of Lrrk2supporting

confidence: 53%

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

Seol

2010

BMB Reports

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Parkinson's disease (PD) is the second most common neurodegenerative disease, and 5-10% of the PD cases are genetically inherited as familial PD (FPD). LRRK2 (leucine-rich repeat kinase 2) was first reported in 2004 as a gene corresponding to PARK8, an autosomal gene whose dominant mutations cause familial PD. LRRK2 contains both active kinase and GTPase domains as well as protein-protein interaction motifs such as LRR (leucine-rich repeat) and WD40. Most pathogenic LRRK2 mutations are located in either the GTPase or kinase domain, implying important roles for the enzymatic activities in PD pathogenic mechanisms. In comparison to other PD causative genes such as parkin and PINK1, LRRK2 exhibits two important features. One is that LRRK2's mutations (especially the G2019S mutation) were observed in sporadic as well as familial PD patients. Another is that, among the various PDcausing genes, pathological characteristics observed in patients carrying LRRK2 mutations are the most similar to patients with sporadic PD. Because of these two observations, LRRK2 has been intensively investigated for its pathogenic mechanism (s) and as a target gene for PD therapeutics. In this review, the general biochemical and molecular features of LRRK2, the recent results of LRRK2 studies and LRRK2's therapeutic potential as a PD target gene will be discussed. [BMB reports 2010; 43(4): 233-244]

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Section: Normal and Pathological Features Of Lrrk2supporting

confidence: 53%

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

Seol

2010

BMB Reports

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“…Lower urate levels have been associated with higher risk of PD, as well as more rapid clinical progression of PD (5,6) and possibly other neurodegenerative diseases (22,23). Similarly, lower urate levels have been consistently reported in PD patients compared with control subjects (24,25). However, no experimental evidence has directly linked hypouricemia to neurodegeneration in vivo.…”

Section: Discussionmentioning

confidence: 99%

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Chen

Burdett

Desjardins

et al. 2012

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

112

121

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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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“…Indeed, plasma or serum urate levels are lower in people with PD [44,45] and ALS [46,47] than healthy controls. Further, in postmortem substantia nigra tissue, urate levels are lower in patients with PD than in age-matched controls [12].…”

Section: Urate and Its Determinants Are A Risk Factor For Neurodegenementioning

confidence: 95%

“…Early work in PD postmortem tissue demonstrated low levels of the antioxidant urate in the substantia nigra [12] and high urate levels were found to be associated with reduced risk of later developing PD [13]. Since these early observations, rapidly accumulating epidemiological studies, laboratory data, and early clinical trial results (summarized below and in Table 1) have provided substantial support for a neuroprotective role of urate and its potential as a disease biomarker.…”

Section: Introductionmentioning

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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Uric acid is reduced in the substantia nigra in parkinson's disease: Effect on dopamine oxidation

Cited by 142 publications

References 51 publications

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

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