Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease

Duan, Wenzhen; Ladenheim, Bruce; Cutler, Roy G.; Kruman, Inna I.; Cadet, Jean Lud; Mattson, Mark P.

doi:10.1046/j.0022-3042.2001.00676.x

Cited by 365 publications

(264 citation statements)

References 54 publications

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“…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]. Similarly, in a rotenone toxicity model, urate prevented death of dopaminergic cells [52]. At physiologically relevant concentrations, urate was also shown to enhance function and survival of dopaminergic neurons in primary cultures of rat ventral mesencephalon [53].…”

Section: Urate Is Neuroprotective In Several Preclinical Models Of Nesupporting

confidence: 90%

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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Section: Urate Is Neuroprotective In Several Preclinical Models Of Nesupporting

confidence: 90%

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

Paganoni

Schwarzschild

2017

Neurotherapeutics

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“…Urate blocked DA-induced apoptotic cell death, and it protected against 6-OHDA toxicity in PC12 cells (18,19). In dopaminergic neurons, it reduced mitochondrial dysfunction and cell death occurring spontaneously in culture or induced by pesticides rotenone or iron ions (20,21). We report here that UOx KO mice are more resistant to 6-OHDA neurotoxicity.…”

Section: Discussionmentioning

confidence: 57%

“…Urate is a potent antioxidant, and antioxidant properties of urate have been proposed to mediate its neuroprotective effects in most aforementioned studies (13)(14)(15)(16)(17)(18)(19)(20)(21). We investigated oxidative stress status in UOx KO and Tg mice and found higher protein carbonyls, one of the most commonly used markers of oxidative stress, in both.…”

Section: Discussionmentioning

confidence: 92%

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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“…Previous studies have failed to detect neuronal cell death in the hippocampus of WT mice fed hyperhomocysteinemiainducing diets (38,39). Indeed, even the direct injection of a large dose of homocysteine into the hippocampus of WT mice did not kill neurons (40).…”

Section: Hippocampal Capillary Length (Micron)mentioning

confidence: 96%

“…Indeed, even the direct injection of a large dose of homocysteine into the hippocampus of WT mice did not kill neurons (40). Dietary hyperhomocysteinemia has only been found to enhance neuronal cell death in mice that are predisposed to neurodegeneration, such as the transgenic mutant amyloid precursor protein model of Alzheimer's disease (38) or in mice rendered pharmacologically susceptible to Parkinson's disease (39). Similarly, feeding neurocompromised Apolipoprotein E-deficient mice B-vitamin-deficient diets induces both hyperhomocysteinemia and cognitive impairment without neurodegeneration, astrogliosis, or demyelination (10).…”

Section: Hippocampal Capillary Length (Micron)mentioning

confidence: 99%

B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice

Troen

Shea‐Budgell²,

Shukitt‐Hale³

et al. 2008

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

166

133

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In older adults, mildly elevated plasma total homocysteine (hyperhomocysteinemia) is associated with increased risk of cognitive impairment, cerebrovascular disease, and Alzheimer's disease, but it is uncertain whether this is due to underlying metabolic, neurotoxic, or vascular processes. We report here that feeding male C57BL6/J mice a B-vitamin-deficient diet for 10 weeks induced hyperhomocysteinemia, significantly impaired spatial learning and memory, and caused a significant rarefaction of hippocampal microvasculature without concomitant gliosis and neurodegeneration. Total hippocampal capillary length was inversely correlated with Morris water maze escape latencies (r ‫؍‬ ؊0.757, P < 0.001), and with plasma total homocysteine (r ‫؍‬ ؊0.631, P ‫؍‬ 0.007). Feeding mice a methionine-rich diet produced similar but less pronounced effects. Our findings suggest that cerebral microvascular rarefaction can cause cognitive dysfunction in the absence of or preceding neurodegeneration. Similar microvascular changes may mediate the association of hyperhomocysteinemia with human age-related cognitive decline. cerebrovascular ͉ homocysteine ͉ mouse ͉ nutrition

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Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease

Cited by 365 publications

References 54 publications

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration

B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice

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