创伤性脑损伤后rho相关卷曲蛋白激酶1的失调消耗神经干细胞库并损害海马神经发生

IF 5.6 1区 生物学 Q2 CELL BIOLOGY
Chaoqun Yao, Long Jin, Jun Zhong, Qianying Huang, Zhongwei Bao, Shaolong Zhou, Chaohua Wang, Huanhuan Li, Xiaowei Yuan, Zhen Wang, Ning Du, Jingxuan Yu, Huanran Chen, Xuyang Zhang, Hongfei Ge, Jianheng Wu
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引用次数: 0

摘要

外伤性脑损伤(TBI)是一种全球性的健康负担,往往由于海马神经发生受损而导致持续的神经功能缺损。然而,脑外伤后神经发生的时间进展及其分子机制仍不清楚。探讨脑外伤后海马神经发生损伤和神经功能缺损的机制。采用单细胞RNA测序(scRNA-seq)技术探讨小鼠脑外伤后海马神经发生异常的机制。应用拮抗剂和条件基因敲除(CKO)策略来剖析靶基因的分子功能。在这里,我们发现神经干细胞(NSCs)在TBI早期在海马中被过度激活,随后NSC池逐渐耗尽,神经发生受损,并出现进行性认知功能障碍。ScRNA-seq转录组学分析显示,脑外伤后海马NSCs中rho相关卷曲蛋白激酶1 (ROCK1)持续上调。药理抑制ROCK1或ROCK1 CKO可挽救脑外伤小鼠的慢性神经源性缺陷并改善认知功能。从机制上讲,ROCK1失调通过AKT异常过度磷酸化来破坏神经发生,在成人海马神经发生中建立了单向的ROCK1-AKT信号轴。我们的研究结果表明,ROCK1是TBI后NSC池过度激活和异常神经发生的关键调节因子,并提出了靶向激酶抑制策略作为减轻TBI患者异常神经发生的潜在治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Dysregulation of Rho-Associated Coiled-Coil Protein Kinase1 Depletes Neural Stem Cell Pool and Impairs Hippocampal Neurogenesis After Traumatic Brain Injury.

Traumatic brain injury (TBI) represents a global health burden, often resulting in persistent neurological deficits due to impaired hippocampal neurogenesis. Nevertheless, the temporal progression of post-TBI neurogenesis and its molecular mechanisms remain elusive. To investigate the mechanism of impaired hippocampal neurogenesis and neurological deficits following TBI. Single-cell RNA sequencing (scRNA-seq) was employed to explore the mechanism of abnormal hippocampal neurogenesis after TBI in mice. Antagonists and conditional gene knockout (CKO) strategies were applied to dissect the molecular function of target genes. Here, we found that neural stem cells (NSCs) were hyperactivated as observed in Nestin-GFP reporter mice in hippocampus during the early phases of TBI, followed by progressive depletion of the NSC pool, impaired neurogenesis, and the onset of progressive cognitive dysfunction. ScRNA-seq transcriptomic analysis revealed sustained upregulation of Rho-associated coiled-coil protein kinase 1 (ROCK1) in hippocampal NSCs post-TBI. Pharmacological inhibition of ROCK1 or ROCK1 CKO rescued chronic neurogenic deficits and improved cognitive functions in TBI mice. Mechanistically, ROCK1 dysregulation impaired neurogenesis via aberrant AKT hyperphosphorylation, establishing a unidirectional ROCK1-AKT signalling axis in adult hippocampal neurogenesis. Our findings position ROCK1 as a pivotal regulator of the post-TBI NSC pool hyperactivation and aberrant neurogenesis and propose targeted kinase inhibition strategies as a potential therapy to mitigate abnormal neurogenesis in TBI patients.

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来源期刊
Cell Proliferation
Cell Proliferation 生物-细胞生物学
CiteScore
14.80
自引率
2.40%
发文量
198
审稿时长
1 months
期刊介绍: Cell Proliferation Focus: Devoted to studies into all aspects of cell proliferation and differentiation. Covers normal and abnormal states. Explores control systems and mechanisms at various levels: inter- and intracellular, molecular, and genetic. Investigates modification by and interactions with chemical and physical agents. Includes mathematical modeling and the development of new techniques. Publication Content: Original research papers Invited review articles Book reviews Letters commenting on previously published papers and/or topics of general interest By organizing the information in this manner, readers can quickly grasp the scope, focus, and publication content of Cell Proliferation.
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