Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Exp Neurol. 2024 Jul;377:114778. doi: 10.1016/j.expneurol.2024.114778. Epub 2024 Apr 11.
Neuronal apoptosis is a common pathological change in early brain injury after subarachnoid hemorrhage (SAH), and it is closely associated with neurological deficits. According to previous research, p97 exhibits a remarkable anti-cardiomyocyte apoptosis effect. p97 is a critical molecule in the growth and development of the nervous system. However, it remains unknown whether p97 can exert an anti-neuronal apoptosis effect in SAH. In the present study, we examined the role of p97 in neuronal apoptosis induced after SAH and investigated the underlying mechanism. We established an in vivo SAH mice model and overexpressed the p97 protein through transfection of the mouse cerebral cortex. We analyzed the protective effect of p97 on neurons and evaluated short-term and long-term neurobehavior in mice after SAH. p97 was found to be significantly downregulated in the cerebral cortex of the affected side in mice after SAH. The site showing reduced p97 expression also exhibited a high level of neuronal apoptosis. Adeno-associated virus-mediated overexpression of p97 significantly reduced the extent of neuronal apoptosis, improved early and long-term neurological function, and repaired the neuronal damage in the long term. These neuroprotective effects were accompanied by enhanced proteasome function and inhibition of the integrated stress response (ISR) apoptotic pathway involving eIF2α/CHOP. The administration of the p97 inhibitor NMS-873 induced a contradictory effect. Subsequently, we observed that inhibiting the function of the proteasome with the proteasome inhibitor PS-341 blocked the anti-neuronal apoptosis effect of p97 and enhanced the activation of the ISR apoptotic pathway. However, the detrimental effects of NMS-873 and PS-341 in mice with SAH were mitigated by the administration of the ISR inhibitor ISRIB. These results suggest that p97 can promote neuronal survival and improve neurological function in mice after SAH. The anti-neuronal apoptosis effect of p97 is achieved by enhancing proteasome function and inhibiting the overactivation of the ISR apoptotic pathway.
神经元凋亡是蛛网膜下腔出血（SAH）后早期脑损伤的一种常见病理变化，与神经功能缺损密切相关。既往研究表明，p97 对心肌细胞凋亡具有显著的抑制作用。p97 是神经系统生长发育的关键分子。然而，p97 是否能在 SAH 中发挥抗神经元凋亡作用尚不清楚。本研究探讨了 p97 在 SAH 后神经元凋亡中的作用及其潜在机制。我们建立了体内 SAH 小鼠模型，并通过转染小鼠大脑皮层过表达 p97 蛋白。分析了 p97 对神经元的保护作用，并评估了 SAH 后小鼠的短期和长期神经行为。结果发现，SAH 后小鼠大脑皮层受影响侧 p97 表达明显下调，p97 表达降低的部位神经元凋亡水平较高。腺相关病毒介导的 p97 过表达显著减轻了神经元凋亡的程度，改善了早期和长期神经功能，并在长期内修复了神经元损伤。这些神经保护作用伴随着蛋白酶体功能的增强和抑制涉及 eIF2α/CHOP 的整合应激反应（ISR）凋亡途径。p97 抑制剂 NMS-873 的给药则产生了相反的效果。随后，我们观察到用蛋白酶体抑制剂 PS-341 抑制蛋白酶体的功能阻断了 p97 的抗神经元凋亡作用，并增强了 ISR 凋亡途径的激活。然而，用 ISR 抑制剂 ISRIB 处理 SAH 小鼠可以减轻 NMS-873 和 PS-341 的有害作用。这些结果表明，p97 可以促进 SAH 后小鼠神经元的存活和改善神经功能。p97 的抗神经元凋亡作用是通过增强蛋白酶体功能和抑制 ISR 凋亡途径的过度激活来实现的。
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