Live imaging reveals the cellular events downstream of SARM1 activation
- Washington University School of Medicine, United States
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.
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All data generated or analyzed during this study are included in the manuscript and supporting files.
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Funding
National Institutes of Health (R01CA219866)
- Jeffrey Milbrandt
- Aaron DiAntonio
National Institutes of Health (RO1NS087632)
- Jeffrey Milbrandt
- Aaron DiAntonio
National Institutes of Health (RF1-AG013730)
- Jeffrey Milbrandt
National Institutes of Health (F32NS117784)
- Laura Devault
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Ko et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Live imaging reveals the cellular events downstream of SARM1 activation
eLife 10:e71148.
https://doi.org/10.7554/eLife.71148
