Live imaging reveals the cellular events downstream of SARM1 activation

eLife

Aaron DiAntonio¹  Jeffrey Milbrandt²  Yo Sasaki³  Kwang Woo Ko⁴  Laura Devault⁴ 

[1] Developmental Biology, Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St Louis, United States;Genetics, Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, United States;Genetics, Washington University School of Medicine, St Louis, United States;Washington University School of Medicine, St Louis, United States;

关键词: SARM1;    calcium;    mitochondria;    NAD+;    Mouse;   

DOI  :  10.7554/eLife.71148

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY