Abstract
Considerable evidence has shown that elevated plasma or cerebrospinal fluid (CSF) urate levels correlated with a reduced risk of Parkinson’s disease (PD). Based on its anti-oxidative properties, urate might serve as one of promising neuroprotective candidates for PD. However, how urate is transported through cell membranes to exert its effects inside the cells in PD is largely unknown. To elucidate this, we showed that increased intracellular urate exerted its neuroprotective effects against 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in MES23.5 cells and elevated urate could antagonize 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic neuronal death in urate oxidase (UOx) knockout (KO) mice. Its transporter, glucose transporter type 9 (Glut9), was observed up-regulated, which was caused by the activation of p53. These protective effects could be abolished by Glut9 blocker and p53 inhibitor. These results suggested that Glut9 was a functional urate transporter, whose up-regulation by activation of p53 resulted in the increased intracellular urate levels in PD models. Our findings suggest that Glut9 could be modified to modulate urate levels in dopaminergic neurons and urate-elevating strategies without increasing systemic levels to avoid side effects might serve as a potential therapeutic target for PD.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN) and subsequent dopamine depletion in the striatum (Hornykiewicz, 1998; Song et al, 2017)
Considering that 50 μM MPP+ reduced cell viability by 35.6% compared with the control, which was the minimum concentration to cause cell damage, 50 μM MPP+ was chosen for the following experiments
The results showed that urate did not produce any toxic effects on MES23.5 cells except for the highest concentration used (1000 μM; Figure 1C)
Summary
Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN) and subsequent dopamine depletion in the striatum (Hornykiewicz, 1998; Song et al, 2017). Glut9-mediated Urate Transport in Parkinson’s Disease evidence indicates that oxidative stress is a major contributor in the pathogenesis of PD (Jenner and Olanow, 1998; Schapira et al, 1998), suggesting that antioxidants could have some potential usages in PD treatment. High plasma urate levels are risk factors for several metabolic syndromes, such as gout and type 2 diabetes mellitus, they could decrease the incidence of PD and its progression (Hayden and Tyagi, 2004; Schwarzschild et al, 2008; Ascherio et al, 2009). Subsequent epidemiological and experimental studies all suggest that higher dietary urate intake or early diagnosis of gout has a lower risk of PD (Alonso et al, 2007; Gao et al, 2008). Reduced urate levels in the SN have been observed prior to clinical symptoms in PD patients (Church and Ward, 1994), which is more likely a predictor of PD diagnosis in the prodromal phase and neuroprotective intervention before the onset of neurological symptoms (Fang et al, 2013; Ascherio and Schwarzschild, 2016)
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