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与ALS相关的C9orf72-SMCR8复合体是初级纤毛发育的负调节者

Dan Tang¹, Kaixuan Zheng¹, Jiangli Zhu^1,2

¹Department of Urology, Institute of Urology, State Key Laboratory of Biotherapy, West China Hospital, College of Life Sciences, Sichuan University, and National Collaborative Innovation Center, Chengdu 610041, People's Republic of China.

Proceedings of the National Academy of Sciences of the United States of America

|December 8, 2023

概括

C9orf72-SMCR8复合体通过作为RAB8A GTPase激活蛋白来负面调节一次性纤维生成. 这种复合体的丧失会影响纤毛发育,并可能导致神经退行性疾病.

科学领域:

分子生物学分子生物学
神经科学是一个神经科学.
细胞生物学细胞生物学

背景情况:

在C9orf72中GGGGCC (G4C2) 重复的扩展与遗传性肌缩侧面硬化症和前性痴呆症有关.
C9orf72蛋白的精确生物功能在很大程度上是未知的.
C9orf72与SMCR8形成一个功能复合体,被确定为GTPase激活蛋白 (GAP).

研究的目的:

为了阐明C9orf72-SMCR8复合物的生物功能.
调查C9orf72-SMCR8在初级纤毛发育和相关疾病中的作用.

主要方法:

生物化学分析以确定C9orf72-SMCR8复合体内的子单元功能.
在多个小鼠组织中调查该复合体在初级纤毛发育中的作用.
基因淘汰研究 (C9orf72或SMCR8) 评估细胞反应,特别是对鼠信号的反应.

主要成果:

C9orf72-SMCR8复合体作为一次性纤维形成的主要负调节剂.
该复合体作为RAB8A GTPase激活蛋白 (GAP) 起作用,其中C9orf72结合RAB8A和SMCR8提供GAP活性.
丧失C9orf72或SMCR8功能会导致对刺信号的敏感性增加,并影响大脑,脏和脏组织的纤维生成.

结论:

C9orf72在调节初级纤毛发育过程中起着至关重要的,以前未被认可的作用.
C9orf72-SMCR8复合体的失调会影响纤毛发育,并为C9orf72相关的神经退行性疾病的发病提供了洞察力.
这些发现突出了一个新的机制,将C9orf72功能与纤毛病和神经退行症联系起来.

关键词:

C9orf7272 是一个很好的方法.在这个问题上,GAP GAP.在SMCR8中,膜贩运贩卖贩卖贩卖贩卖贩卖贩卖主要的纤毛是主要的纤毛.

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