Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in alpha-synuclein overexpressing mice.
Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in alpha-synuclein overexpressing mice.
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DOI：
10.1371/journal.pone.0012333
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发表时间：
2010-08-23
期刊：
影响因子：
3.7
通讯作者：
Simon DK
中科院分区：
文献类型：
--
作者：
Clark J;Clore EL;Zheng K;Adame A;Masliah E;Simon DK
在帕金森病（PD）早期，黑质（SN）中谷胱甘肽水平较低，这可能导致线粒体功能障碍和氧化应激。氧化应激可能会增加α-突触核蛋白（SNCA）毒性形式的积累。我们假设补充n-乙酰半胱氨酸（NAC）（半胱氨酸的一种来源，半胱氨酸是谷胱甘肽合成中的限制性氨基酸）可以防止α-突触核蛋白毒性。过度表达野生型人α-突触核蛋白的转基因小鼠从6周龄至1岁饮用补充有NAC的水或补充有丙氨酸的对照水。NAC在治疗的5-7周内增加了谷胱甘肽的SN水平;然而，这种增加在1年时没有持续。尽管NAC对脑谷胱甘肽的影响是短暂的，但通过纹状体中酪氨酸羟化酶的免疫反应性（p = 0.007;非配对，双尾t检验）测定，NAC补充显著减弱了1年时与SNCA过表达相关的多巴胺能末梢的丧失，多巴胺转运蛋白（DAT）免疫反应性具有相似但不显著的趋势。 与丙氨酸处理的转基因小鼠相比，NAC显著降低了PDGFb-SNCA转基因小鼠脑中人SNCA的水平。这与NAC处理的转基因细胞中NF κB核定位的减少和NFκB胞浆定位的增加有关。总体而言，这些结果表明，口服NAC补充剂降低了脑中的SNCA水平，并在该模型中部分防止了与α-突触核蛋白过表达相关的多巴胺能末梢的丢失。
Levels of glutathione are lower in the substantia nigra (SN) early in Parkinson's disease (PD) and this may contribute to mitochondrial dysfunction and oxidative stress. Oxidative stress may increase the accumulation of toxic forms of α-synuclein (SNCA). We hypothesized that supplementation with n-acetylcysteine (NAC), a source of cysteine – the limiting amino acid in glutathione synthesis, would protect against α-synuclein toxicity. Transgenic mice overexpressing wild-type human α-synuclein drank water supplemented with NAC or control water supplemented with alanine from ages 6 weeks to 1 year. NAC increased SN levels of glutathione within 5–7 weeks of treatment; however, this increase was not sustained at 1 year. Despite the transient nature of the impact of NAC on brain glutathione, the loss of dopaminergic terminals at 1 year associated with SNCA overexpression was significantly attenuated by NAC supplementation, as measured by immunoreactivity for tyrosine hydroxylase in the striatum (p = 0.007; unpaired, two-tailed t-test), with a similar but nonsignificant trend for dopamine transporter (DAT) immunoreactivity. NAC significantly decreased the levels of human SNCA in the brains of PDGFb-SNCA transgenic mice compared to alanine treated transgenics. This was associated with a decrease in nuclear NFκB localization and an increase in cytoplasmic localization of NFκB in the NAC-treated transgenics. Overall, these results indicate that oral NAC supplementation decreases SNCA levels in brain and partially protects against loss of dopaminergic terminals associated with overexpression of α-synuclein in this model.
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DOI：
10.1016/s0925-4439(97)00070-7
发表时间：
1997-11-28
影响因子：
6.2
作者：
Cassarino, DS;Fall, CP;Bennett, JP
通讯作者：
Bennett, JP
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
56.9
作者：
Conway, KA;Rochet, JC;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
6
作者：
Duda, JE;Giasson, BI;Trojanowski, JQ
通讯作者：
Trojanowski, JQ
影响因子：
168.9
作者：
Ibáñez, P;Bonnet, AM;Brice, A
通讯作者：
Brice, A