气候变化领域集成服务门户(CCPortal): Ras-like Gem GTPase induced by Npas4 promotes activity-dependent neuronal tolerance for ischemic stroke

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DOI	10.1073/pnas.2018850118
	Ras-like Gem GTPase induced by Npas4 promotes activity-dependent neuronal tolerance for ischemic stroke
	Takahashi H.; Asahina R.; Fujioka M.; Matsui T.K.; Kato S.; Mori E.; Hioki H.; Yamamoto T.; Kobayashi K.; Tsuboi A.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:32
英文摘要	Ischemic stroke, which results in loss of neurological function, initiates a complex cascade of pathological events in the brain, largely driven by excitotoxic Ca2+influx in neurons. This leads to cortical spreading depolarization, which induces expression of genes involved in both neuronal death and survival; yet, the functions of these genes remain poorly understood. Here, we profiled gene expression changes that are common to ischemia (modeled by middle cerebral artery occlusion [MCAO]) and to experiencedependent activation (modeled by exposure to an enriched environment [EE]), which also induces Ca2+transients that trigger transcriptional programs. We found that the activity-dependent transcription factor Npas4 was up-regulated under MCAO and EE conditions and that transient activation of cortical neurons in the healthy brain by the EE decreased cell death after stroke. Furthermore, both MCAO in vivo and oxygen-glucose deprivation in vitro revealed that Npas4 is necessary and sufficient for neuroprotection. We also found that this protection involves the inhibition of L-type voltage-gated Ca2+channels (VGCCs). Next, our systematic search for Npas4-downstream genes identified Gem, which encodes a Ras-related small GTPase that mediates neuroprotective effects of Npas4. Gem suppresses the membrane localization of L-type VGCCs to inhibit excess Ca2+influx, thereby protecting neurons from excitotoxic death after in vitro and in vivo ischemia. Collectively, our findings indicate that Gem expression via Npas4 is necessary and sufficient to promote neuroprotection in the injured brain. Importantly, Gem is also induced in human cerebral organoids cultured under an ischemic condition, revealing Gem as a new target for drug discovery. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Ischemic stroke; Neural activity-dependent; Neuroplasticity; Neuroprotection; Npas4
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238836
作者单位	Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Kagawa, 761-0793, Japan; Laboratory for Molecular Biology of Neural Systems, Advanced Medical Research Center, Nara Medical University, Nara, 634-8521, Japan; Department of Future Basic Medicine, School of Medicine, Nara Medical University, Nara, 634-8521, Japan; Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University, Fukushima, 960-1295, Japan; Department of Cell Biology and Neuroscience, School of Medicine, Juntendo University, Tokyo, 113-8421, Japan; Laboratory for Cellular and Molecular Neurobiology, Graduate School of Frontier Biosciences, Osaka University, Suita, 565-0871, Japan
推荐引用方式 GB/T 7714	Takahashi H.,Asahina R.,Fujioka M.,et al. Ras-like Gem GTPase induced by Npas4 promotes activity-dependent neuronal tolerance for ischemic stroke[J],2021,118(32).
APA	Takahashi H..,Asahina R..,Fujioka M..,Matsui T.K..,Kato S..,...&Tsuboi A..(2021).Ras-like Gem GTPase induced by Npas4 promotes activity-dependent neuronal tolerance for ischemic stroke.Proceedings of the National Academy of Sciences of the United States of America,118(32).
MLA	Takahashi H.,et al."Ras-like Gem GTPase induced by Npas4 promotes activity-dependent neuronal tolerance for ischemic stroke".Proceedings of the National Academy of Sciences of the United States of America 118.32(2021).