Effect of the cross-talk between autophagy and endoplasmic reticulum stress on Mn-induced alpha-synuclein oligomerization
Effect of the cross-talk between autophagy and endoplasmic reticulum stress on Mn-induced alpha-synuclein oligomerization
复制标题
自噬和内质网应激之间的串扰对锰诱导的α-突触核蛋白寡聚化的影响
DOI：
10.1002/tox.22518
复制
发表时间：
2018-03-01
影响因子：
4.5
通讯作者：
Xu, Bin
中科院分区：
文献类型：
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作者：
Liu, Chang;Yan, Dong-Ying;Xu, Bin
已知过量暴露于锰可诱导α-突触核蛋白(α-Syn)寡聚，其降解主要依赖于内质网应激(内质网应激)和自噬途径。然而，很少有数据报道内质网应激和自噬之间在锰诱导的α-Syn寡聚中的相互作用。为了探讨内质网应激与自噬的关系，我们在小鼠锰中毒模型上使用了内质网应激抑制剂4-苯丁酸(4-PBA)、自噬激活剂雷帕霉素(Rap)和自噬抑制剂3-甲基腺嘌呤(3-MA)。锰处理4周后，内质网应激和自噬均被激活。染锰还可引起小鼠脑组织α-Syn寡聚和神经细胞损伤，4-PBA可减轻这一损伤。此外，当内质网应激被抑制时，自噬的激活也被抑制。RAP处理可显著激活自噬，减少α-Syn寡聚体的形成。但3-MA可抑制自噬，导致α-Syn寡聚体增加，并代偿激活PERK信号通路。我们的结果还表明，3-MA抑制自噬加重了神经细胞的损伤。这些结果清楚地表明，自噬和内质网应激之间的相互作用可能在锰的α-Syn寡聚和神经毒性中起重要作用。
Overexposure to manganese (Mn) has been known to induce alpha-synuclein (alpha-Syn) oligomerization, which is degraded mainly depending on endoplasmic reticulum stress (ER stress) and autophagy pathways. However, little data reported the cross-talk between ER stress and autophagy on Mn-induced alpha-Syn oligomerization. To explore the relationship between ER stress and autophagy, we used 4-phenylbutyric acid (4-PBA, the ER stress inhibitor), rapamycin (Rap, autophagy activator) and 3-methyladenine (3-MA, autophagy inhibitor) in mice model of manganism. After 4 weeks of treatment with Mn, both ER stress and autophagy were activated. Exposed to Mn also resulted in alpha-Syn oligomerization and neuronal cell damage in the brain tissue of mice, which could be relieved by 4-PBA pretreatment. Moreover, when the ER stress was inhibited, the activation of autophagy was also inhibited. Rap pretreatment significantly activated autophagy and decreased alpha-Syn oligomers. However, 3-MA pretreatment inhibited autophagy resulting in increase of alpha-Syn oligomers, and compensatorily activated PERK signaling pathway. Our results also demonstrated that the inhibition of autophagy by 3-MA aggravated neuronal cell damage. The findings clearly demonstrated that the cross-talking between autophagy and ER stress might play an important role in the alpha-Syn oligomerization and neurotoxicity by Mn.