Urate and its transgenic depletion modulate neuronal vulnerability in a cellular model of Parkinson's disease.
Urate and its transgenic depletion modulate neuronal vulnerability in a cellular model of Parkinson's disease.
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DOI：
10.1371/journal.pone.0037331
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Schwarzschild MA
中科院分区：
文献类型：
--
作者：
Cipriani S;Desjardins CA;Burdett TC;Xu Y;Xu K;Schwarzschild MA
尿酸盐是一种主要的抗氧化剂，也是人体嘌呤代谢的酶促终产物。较高的水平与降低患帕金森病 (PD) 的风险以及减缓帕金森病进展速度相关。在这项研究中，我们研究了调节细胞内尿酸盐浓度对 1-甲基-4-苯基-吡啶鎓 (MPP+) 诱导的小鼠腹侧中脑培养物中多巴胺能神经元变性的影响，所述培养物制备成含有低百分比（富含神经元的培养物）或高百分比（神经元-胶质细胞培养物）的星形胶质细胞。在 MPP+ 治疗前 24 小时和治疗期间将尿酸盐添加到培养物中，可以减轻神经元富集培养物中多巴胺能神经元的损失，并完全防止神经元-星形胶质细胞培养物中多巴胺能神经元的损失和萎缩。发现外源尿酸盐会增加皮质神经元培养物中细胞内尿酸盐的含量。为了评估降低细胞尿酸含量对 MPP+ 诱导的毒性的影响，从过度表达尿酸氧化酶 (UOx) 的小鼠中制备中脑神经元。转基因 UOx 表达降低了神经元和星形胶质细胞中的内源尿酸盐含量。在中脑神经元富集培养物中，表达 UOx 的多巴胺能神经元对 MPP+ 更敏感，在中脑神经元星形胶质细胞培养物中更容易受到 MPP+ 的影响。我们的研究结果将多巴胺能神经元的细胞内尿酸盐含量与其在帕金森病细胞模型中的毒素抵抗性相关联，并表明星形胶质细胞在尿酸盐的神经保护作用中发挥促进作用。
Urate is a major antioxidant as well as the enzymatic end product of purine metabolism in humans. Higher levels correlate with a reduced risk of developing Parkinson's disease (PD) and with a slower rate of PD progression. In this study we investigated the effects of modulating intracellular urate concentration on 1-methyl-4-phenyl-pyridinium (MPP+)-induced degeneration of dopaminergic neurons in cultures of mouse ventral mesencephalon prepared to contain low (neuron-enriched cultures) or high (neuron-glial cultures) percentage of astrocytes. Urate, added to the cultures 24 hours before and during treatment with MPP+, attenuated the loss of dopaminergic neurons in neuron-enriched cultures and fully prevented their loss and atrophy in neuron-astrocyte cultures. Exogenous urate was found to increase intracellular urate content in cortical neuronal cultures. To assess the effect of reducing cellular urate content on MPP+-induced toxicity, mesencephalic neurons were prepared from mice over-expressing urate oxidase (UOx). Transgenic UOx expression decreased endogenous urate content both in neurons and astrocytes. Dopaminergic neurons expressing UOx were more susceptible to MPP+ in mesencephalic neuron-enriched cultures and to a greater extent in mesencephalic neuron-astrocyte cultures. Our findings correlate intracellular urate content in dopaminergic neurons with their toxin resistance in a cellular model of PD and suggest a facilitative role for astrocytes in the neuroprotective effect of urate.
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影响因子：
64.8
作者：
Enomoto, A;Kimura, H;Endou, H
通讯作者：
Endou, H
影响因子：
4.2
作者：
Lee, CS;Han, JH;Han, ES
通讯作者：
Han, ES
DOI：
10.1073/pnas.78.11.6858
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
AMES, BN;CATHCART, R;HOCHSTEIN, P
通讯作者：
HOCHSTEIN, P
影响因子：
3.3
作者：
Aoyama, K.;Matsumura, N.;Nakaki, T.
通讯作者：
Nakaki, T.
影响因子：
1.9
作者：
Andreadou, Elisabeth;Nikolaou, Chryssoula;Vassilopoulos, Demetrios
通讯作者：
Vassilopoulos, Demetrios