p97 inhibits integrated stress response-induced neuronal apoptosis after subarachnoid hemorrhage in mice by enhancing proteasome function

Wenping Cheng; Boyang Wei; Wenchao Liu; Lei Jin; Shenquan Guo; Mingxiang Ding; Yanchao Liu; Haiyan Fan; Ran Li; Xin Zhang; Xuying He; Xifeng Li; Chuanzhi Duan

doi:10.1016/j.expneurol.2024.114778

p97 inhibits integrated stress response-induced neuronal apoptosis after subarachnoid hemorrhage in mice by enhancing proteasome function

Exp Neurol. 2024 Apr 11:377:114778. doi: 10.1016/j.expneurol.2024.114778. Online ahead of print.

Authors

Wenping Cheng¹, Boyang Wei¹, Wenchao Liu¹, Lei Jin¹, Shenquan Guo¹, Mingxiang Ding¹, Yanchao Liu¹, Haiyan Fan¹, Ran Li¹, Xin Zhang¹, Xuying He¹, Xifeng Li², Chuanzhi Duan³

Affiliations

¹ 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.
² 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. Electronic address: nflxf@126.com.
³ 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. Electronic address: doctor_duanzj@163.com.

PMID: 38609045
DOI: 10.1016/j.expneurol.2024.114778

Abstract

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.

Keywords: Apoptosis; Early brain injury; Integrated stress response; Subarachnoid hemorrhage; p97.