Abstract
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 2α kinase (PERK)/eIF2α phosphorylation signaling pathway in Drosophila neurons. Chronic heat-induced eIF2α phosphorylation was regulated by PERK activation and required for neuroprotection from chronic heat stress. Moreover, the attenuated protein synthesis by eIF2α 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 eIF2α phosphorylation mediated by PERK may contribute to the protection of DA neurons against chronic heat stress in Drosophila.
Highlights
Many organisms, including humans, could be influenced by the consequences of the increased temperature of the earth, known as global warming
We previously showed that heat exposure caused a disturbance in proteostasis in the cytosol and in the endoplasmic reticulum (ER), and it subsequently induced unfolded protein response (UPR) signaling in mouse embryo fibroblasts (MEFs) [22]
Our present study showed that long-term and mild heat exposure led to a shortened Drosophila life span with a concomitant induction of ER stress and the UPR
Summary
Many organisms, including humans, could be influenced by the consequences of the increased temperature of the earth, known as global warming. Since high-temperature heat exposure causes protein aggregation and denaturation inside cells, it is likely that heat stress could lead to disturbed proteostasis in the ER [20,21]. We found that chronic heat exposure induced ER stress with subsequent induction of the PERK/eIF2α phosphorylation pathway in Drosophila neuronal cells. Our results showed that PERK is required for phosphorylation of eIF2α in response to chronic heat-induced ER stress activation and the attenuation of global protein translation that occurs in neuronal cells, including DA neurons. Chronic exposure to heat in a Drosophila model may hasten the onset and progression of sporadic PD, and chronic heat-induced activation of ER stress mediated by eIF2α phosphorylation suggests a potential pathological mechanism of PD
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