PERK-Mediated eIF2α Phosphorylation Contributes to The Protection of Dopaminergic Neurons from Chronic Heat Stress in Drosophila
PERK-Mediated eIF2α Phosphorylation Contributes to The Protection of Dopaminergic Neurons from Chronic Heat Stress in Drosophila
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DOI：
10.3390/ijms21030845
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发表时间：
2020-02-01
影响因子：
5.6
通讯作者：
Han, Jaeseok
中科院分区：
文献类型：
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作者：
Elvira, Rosalie;Cha, Sun Joo;Han, Jaeseok
环境高温热暴露与生理应激有关，如内质网（ER）应激引起的蛋白质稳态紊乱。神经细胞蛋白质稳态异常是帕金森病（PD）的常见病理因素。慢性热应激被认为在PD的发病和进展过程中诱导神经元细胞死亡，但ER应激和未折叠蛋白反应（UPR）激活的确切作用和机制尚不清楚。在这里，我们表明，慢性热暴露诱导的内质网应激介导的PKR样真核起始因子2 α激酶（PERK）/eIF 2 α磷酸化信号通路在果蝇神经元。慢性热诱导的eIF 2 α磷酸化受PERK激活调节，并且是慢性热应激的神经保护所必需的。此外，衰减的蛋白质合成eIF 2 α磷酸化是一个关键因素的神经细胞存活在慢性热应激。我们进一步表明，PERK的遗传下调，特别是在多巴胺能（DA）神经元，损害运动活动，并导致DA神经元的损失。因此，我们的研究结果提供了体内证据表明，慢性热暴露可能是一个关键的危险因素，在PD的发病，和eIF 2 α磷酸化介导的PERK可能有助于保护DA神经元对慢性热应激的果蝇。
Environmental high-temperature heat exposure is linked to physiological stress such as disturbed protein homeostasis caused by endoplasmic reticulum (ER) stress. Abnormal proteostasis in neuronal cells is a common pathological factor of Parkinson's disease (PD). Chronic heat stress is thought to induce neuronal cell death during the onset and progression of PD, but the exact role and mechanism of ER stress and the activation of the unfolded protein response (UPR) remains unclear. Here, we showed that chronic heat exposure induces ER stress mediated by the PKR-like eukaryotic initiation factor 2 alpha kinase (PERK)/eIF2 alpha phosphorylation signaling pathway in Drosophila neurons. Chronic heat-induced eIF2 alpha phosphorylation was regulated by PERK activation and required for neuroprotection from chronic heat stress. Moreover, the attenuated protein synthesis by eIF2 alpha phosphorylation was a critical factor for neuronal cell survival during chronic heat stress. We further showed that genetic downregulation of PERK, specifically in dopaminergic (DA) neurons, impaired motor activity and led to DA neuron loss. Therefore, our findings provide in vivo evidence demonstrating that chronic heat exposure may be a critical risk factor in the onset of PD, and eIF2 alpha phosphorylation mediated by PERK may contribute to the protection of DA neurons against chronic heat stress in Drosophila.