Alharbi Bothina Mohammed, Albinhassan Tahani H, Alzahrani Razan Ali, Bouchama Abderrezak, Mohammad Sameer, Alomari Awatif Abdulaziz, Bin-Jumah May Nasser, AlSuhaibani Entissar S, Malik Shuja Shafi
Experimental Medicine Department, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11426, Saudi Arabia.
Zoology Department, College of Science, King Saud University, Riyadh 12372, Saudi Arabia.
Biology (Basel). 2023 Mar 9;12(3):416. doi: 10.3390/biology12030416.
Heat stroke is among the most hazardous hyperthermia-related illnesses and an emerging threat to humans from climate change. Acute brain injury and long-lasting brain damage are the hallmarks of this condition. Hyperthermic neurological manifestations are remarkable for their damage correlation with stress amplitude and long-term persistence. Hyperthermia-induced protein unfolding, and nonspecific aggregation accumulation have neurotoxic effects and contribute to the pathogenesis of brain damage in heat stroke. Therefore, we generated heat-induced, dose-responsive extreme and mild proteotoxic stress models in medulloblastoma [Daoy] and neuroblastoma [SH-SY5Y] and differentiated SH-SY5Y neuronal cells. We show that heat-induced protein aggregation is associated with reduced cell proliferation and viability. Higher protein aggregation in differentiated neurons than in neuroblastoma precursors suggests a differential neuronal vulnerability to heat. We characterized the neuronal heat shock response through RT-PCR array analysis of eighty-four genes involved in protein folding and protein quality control (PQC). We identify seventeen significantly expressed genes, five of which are Hsp70 chaperones, and four of their known complementing function proteins. Protein expression analysis determined the individual differential contribution of the five Hsp70 chaperones to the proteotoxic stress response and the significance of only two members under mild conditions. The co-expression analysis reveals significantly high co-expression between the Hsp70 chaperones and their interacting partners. The findings of this study lend support to the hypothesis that hyperthermia-induced proteotoxicity may underlie the brain injury of heat stroke. Additionally, this study presents a comprehensive map of the Hsp70 network in these models with potential clinical and translational implications.
中暑是与体温过高相关的最危险疾病之一，也是气候变化给人类带来的新威胁。急性脑损伤和持久性脑损伤是这种病症的标志。体温过高引起的神经学表现因其与应激幅度的损伤相关性和长期持续性而显著。体温过高诱导的蛋白质解折叠和非特异性聚集积累具有神经毒性作用，并促成中暑时脑损伤的发病机制。因此，我们在髓母细胞瘤[Daoy]、神经母细胞瘤[SH-SY5Y]以及分化的SH-SY5Y神经元细胞中构建了热诱导、剂量反应性的极端和轻度蛋白毒性应激模型。我们发现热诱导的蛋白质聚集与细胞增殖和活力降低有关。分化神经元中的蛋白质聚集高于神经母细胞瘤前体细胞，这表明神经元对热的易感性存在差异。我们通过对涉及蛋白质折叠和蛋白质质量控制（PQC）的84个基因进行RT-PCR阵列分析，对神经元热休克反应进行了表征。我们鉴定出17个显著表达的基因，其中5个是Hsp70伴侣蛋白，以及4个它们已知的互补功能蛋白。蛋白质表达分析确定了这5个Hsp70伴侣蛋白对蛋白毒性应激反应的个体差异贡献，以及在轻度条件下只有两个成员的重要性。共表达分析揭示了Hsp70伴侣蛋白与其相互作用伙伴之间显著的高共表达。本研究结果支持了体温过高诱导的蛋白毒性可能是中暑脑损伤基础的假说。此外，本研究展示了这些模型中Hsp70网络的全面图谱，具有潜在的临床和转化意义。
