激活SARM1会通过NAD+破坏在局部触发轴突退化
Josiah Gerdts1, E J Brace2, Yo Sasaki1
1Department of Genetics, Washington University Medical School, Saint Louis, MO, USA.
Science (New York, N.Y.)
|April 25, 2015
概括
在受伤后,无菌的α和TIR动机含有1 (SARM1) 蛋白质通过快速分解尼古丁胺氨酸二核酸 (NAD(+)) 来触发轴突退化. 这种NAD(+) 枯竭是轴突自我破坏的关键,可能解释某些突变小鼠的保护机制.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 轴突退化是神经元损伤和疾病中的一个关键过程.
- 无菌α和TIR动机含有1 (SARM1) 蛋白质是轴突退化的关键调节者.
- 了解SARM1的机制对于开发治疗策略至关重要.
研究的目的:
- 阐明SARM1启动轴突退化的分子机制.
- 为了研究尼古丁胺胺氨基二核酸 (NAD(+)) 分解在SARM1介导的轴突损失中的作用.
- 为了确定SARM1活动是否在轴突损伤后至关重要.
主要方法:
- 使用工程蛋白酶敏感SARM1进行活动依赖性研究.
- 研究了SARM1托尔介质蛋白受体 (TIR) 域二元化的作用.
- 测量了SARM1激活和NAD合成的NAD+) 水平和轴突完整性.
- 在Wallerian退化缓慢 (Wld(s)) 突变小鼠的背景下检查了SARM1功能.
主要成果:
- 在轴突受伤后需要SARM1活性来触发退化.
- SARM1 TIR域的二元化足以启动本地轴突退化.
- 激活SARM1导致NAD的快速分解.
- 增加NAD ((+) 合成可以抵消SARM1诱导的轴突破坏.
结论:
- 通过局部程序,SARM1启动了轴突退化,涉及到快速的NAD(+) 耗尽.
- 通过SARM1介导的NAD(+) 的分解是轴突自我破坏的关键步骤.
- 这种NAD (+) 枯竭机制可能是Wld () 突变小鼠中观察到的保护作用的基础.
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