Live imaging reveals the cellular events downstream of SARM1 activation

Author:

Ko Kwang Woo1,Devault Laura1,Sasaki Yo2ORCID,Milbrandt Jeffrey3,DiAntonio Aaron4ORCID

Affiliation:

1. Washington University School of Medicine

2. Genetics, Washington University School of Medicine

3. Genetics, Hope Center for Neurological Disorders, Washington University School of Medicine

4. Developmental Biology, Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine

Abstract

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.

Funder

National Institutes of Health

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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