Rasd1 is involved in white matter injury through neuron-oligodendrocyte communication after subarachnoid hemorrhage

作者全名："Fu, Wenqiao; Che, Xudong; Tan, Jiahe; Cui, Shizhen; Ma, Yinrui; Xu, Daiqi; Long, Haibo; Yang, Xiaolin; Wen, Tangmin; He, Zhaohui"

作者地址："[Fu, Wenqiao; Che, Xudong; Tan, Jiahe; Cui, Shizhen; Ma, Yinrui; Xu, Daiqi; Long, Haibo; Yang, Xiaolin; Wen, Tangmin; He, Zhaohui] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurosurg, Chongqing, Peoples R China; [He, Zhaohui] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurosurg, Chongqing 400016, Peoples R China"

通信作者："He, ZH (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Neurosurg, Chongqing 400016, Peoples R China."

来源：CNS NEUROSCIENCE & THERAPEUTICS

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001068112100001

JCR分区：Q1

影响因子：4.8

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：ferroptosis; neuroinflammation; Rasd1; subarachnoid hemorrhage; white matter injury

摘要："AimsRasd1 has been reported to be correlated with neurotoxicity, metabolism, and rhythm, but its effect in case of subarachnoid hemorrhage (SAH) remained unclear. White matter injury (WMI) and ferroptosis participate in the early brain injury (EBI) after SAH. In this work, we have investigated whether Rasd1 can cause ferroptosis and contribute to SAH-induced WMI.MethodsLentivirus for Rasd1 knockdown/overexpression was administrated by intracerebroventricular (i.c.v) injection at 7 days before SAH induction. SAH grade, brain water content, short- and long-term neurobehavior, Western blot, real-time PCR, ELISA, biochemical estimation, immunofluorescence, diffusion tensor imaging (DTI), and transmission electron microscopy (TEM) were systematically performed. Additionally, genipin, a selective uncoupling protein 2(UCP2) inhibitor, was used in primary neuron and oligodendrocyte co-cultures for further in vitro mechanistic studies.ResultsRasd1 knockdown has improved the neurobehavior, glia polarization, oxidative stress, neuroinflammation, ferroptosis, and demyelination. Conversely, Rasd1 overexpression aggravated these changes by elevating the levels of reactive oxygen species (ROS), inflammatory cytokines, MDA, free iron, and NCOA4, as well as contributing to the decrease of the levels of UCP2, GPX4, ferritin, and GSH mechanistically. According to the in vitro study, Rasd1 can induce oligodendrocyte ferroptosis through inhibiting UCP2, increasing reactive oxygen species (ROS), and activating NCOA4-mediated ferritinophagy.ConclusionsIt can be concluded that Rasd1 exerts a modulated role in oligodendrocytes ferroptosis in WMI following SAH. Rasd1 is mainly located in neurons after SAH. Rasd1 significantly inhibits UCP2 functions and induces ROS levels elevated. Subsequently, such changes trigger glia activation and oxidative stress and finally result in increasing NCOA4-mediated ferritinophagy in oligodendrocytes and causes ferroptosis. Ferroptosis of oligodendrocytes contributes to white matter injury in EBI following SAH.image"

基金机构：National Natural Science Foundation of China

基金资助正文：National Natural Science Foundation of China