Live imaging reveals the cellular events downstream of SARM1 activation.
Live imaging reveals the cellular events downstream of SARM1 activation.
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DOI：
10.7554/elife.71148
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发表时间：
2021-11-15
期刊：
影响因子：
7.7
通讯作者：
DiAntonio A
中科院分区：
文献类型：
--
作者：
Ko KW;Devault L;Sasaki Y;Milbrandt J;DiAntonio A
SARM 1是一种可诱导的NAD+水解酶，在受损和患病的神经系统中触发轴突损失和神经元细胞死亡。虽然SARM 1的激活和酶的功能是明确的，但SARM 1活性下游但轴突死亡之前的细胞事件还不太清楚。损伤的轴突中发生钙、线粒体、ATP和膜稳态的缺陷，但这些事件之间的关系一直难以理清，因为先前的研究分析了大量轴突，其中细胞事件异步发生。在这里，我们使用单轴突分辨率的小鼠感觉神经元的实时成像来研究SARM 1活性下游的细胞事件。我们的研究支持一种模型，其中SARM 1 NAD酶活性导致从细胞ATP损失到线粒体运动和去极化缺陷的有序事件序列，随后是钙内流、磷脂酰丝氨酸的外化和灾难性轴突自我破坏之前的膜通透性损失。
SARM1 is an inducible NAD+ hydrolase that triggers axon loss and neuronal cell death in the injured and diseased nervous system. While SARM1 activation and enzyme function are well defined, the cellular events downstream of SARM1 activity but prior to axonal demise are much less well understood. Defects in calcium, mitochondria, ATP, and membrane homeostasis occur in injured axons, but the relationships among these events have been difficult to disentangle because prior studies analyzed large collections of axons in which cellular events occur asynchronously. Here, we used live imaging of mouse sensory neurons with single axon resolution to investigate the cellular events downstream of SARM1 activity. Our studies support a model in which SARM1 NADase activity leads to an ordered sequence of events from loss of cellular ATP, to defects in mitochondrial movement and depolarization, followed by calcium influx, externalization of phosphatidylserine, and loss of membrane permeability prior to catastrophic axonal self-destruction.