Paraquat, but not maneb, induces synucleinopathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways.
Paraquat, but not maneb, induces synucleinopathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways.
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DOI：
10.1371/journal.pone.0030745
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Sidhu A
中科院分区：
文献类型：
--
作者：
Wills J;Credle J;Oaks AW;Duka V;Lee JH;Jones J;Sidhu A
SNCA和MAPT基因以及环境因素是帕金森病的重要危险因素，帕金森病是第二常见的神经退行性疾病。农用化学品甘露糖和百草枯通过不明确的机制选择性地靶向多巴胺能神经元，导致帕金森氏症。在目前的研究中，我们分析了甘露醇和百草枯单独和联合使用在野生型小鼠中诱发联核症和变态反应的能力。MANEB对提高α-突触核蛋白[α-Syn]或p-Tau水平无效。相比之下，用百草枯治疗的小鼠，通过激活主要的牛磺酸激酶p-α-3β，导致纹状体内GSK-Syn的强劲积聚和牛磺酸的过度磷酸化。与maneb联合治疗并不能增强百草枯的效果。在百草枯处理的小鼠中观察到α-微管蛋白的超乙酰化增加，这表明细胞骨架重塑。百草枯，而不是maneb，抑制了多肽底物上的可溶性蛋白酶体活性，但这与26S蛋白酶体亚单位表达的减少无关。百草枯和maneb处理都增加了自噬抑制因子的水平，哺乳动物雷帕霉素的靶点mTOR，这表明轴突自噬受损，尽管某些自噬蛋白增加，如Beclin 1和Agt12。自噬通量也受到损害，因为处理动物的Lc3 II与Lc3 I的比率降低。人死后帕金森病纹状体的mTOR也增加，其中Lc3 II与Lc3 I的比率降低。热休克蛋白在百草枯处理后增加或不变，这表明伴侣介导的自噬不受农用化学品的阻碍。这些研究为这些农用化学品的作用机制提供了新的见解，表明百草枯的毒性比maneb大得多，它通过抑制蛋白酶体和自噬导致α-syn和p-tau的积累。
SNCA and MAPT genes and environmental factors are important risk factors of Parkinson's disease [PD], the second-most common neurodegenerative disease. The agrichemicals maneb and paraquat selectively target dopaminergic neurons, leading to parkinsonism, through ill-defined mechanisms. In the current studies we have analyzed the ability of maneb and paraquat, separately and together, to induce synucleinopathy and tauopathy in wild type mice. Maneb was ineffective in increasing α-synuclein [α-Syn] or p-Tau levels. By contrast, paraquat treatment of mice resulted in robust accumulation of α-Syn and hyperphosphorylation of Tau in striata, through activation of p-GSK-3β, a major Tau kinase. Co-treatment with maneb did not enhance the effects of paraquat. Increased hyperacetylation of α-tubulin was observed in paraquat-treated mice, suggesting cytoskeleton remodeling. Paraquat, but not maneb, inhibited soluble proteasomal activity on a peptide substrate but this was not associated with a decreased expression of 26S proteasome subunits. Both paraquat and maneb treatments increased levels of the autophagy inhibitor, mammalian target of rapamycin, mTOR, suggesting impaired axonal autophagy, despite increases in certain autophagic proteins, such as beclin 1 and Agt12. Autophagic flux was also impaired, as ratios of LC3 II to LC3 I were reduced in treated animals. Increased mTOR was also observed in postmortem human PD striata, where there was a reduction in the LC3 II to LC3 I ratio. Heat shock proteins were either increased or unchanged upon paraquat-treatment suggesting that chaperone-mediated autophagy is not hampered by the agrichemicals. These studies provide novel insight into the mechanisms of action of these agrichemicals, which indicate that paraquat is much more toxic than maneb, via its inhibitory effects on proteasomes and autophagy, which lead to accumulation of α-Syn and p-Tau.
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影响因子：
4.8
作者：
Hashimoto, M;Bar-on, P;Masliah, E
通讯作者：
Masliah, E
影响因子：
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作者：
Garcia-Arencibia, Moises;Hochfeld, Warren E.;Toh, Pearl P. C.;Rubinsztein, David C.
通讯作者：
Rubinsztein, David C.
影响因子：
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通讯作者：
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