TY - JOUR
T1 - Live imaging reveals the cellular events downstream of sarm1 activation
AU - Ko, Kwang Woo
AU - Devault, Laura
AU - Sasaki, Yo
AU - Milbrandt, Jeffrey
AU - Diantonio, Aaron
N1 - Funding Information:
We thank members of the DiAntonio and Milbrandt labs for fruitful discussions. This work was supported by National Institutes of Health grants R01CA219866 and RO1NS087632 (J M and A D), RF1-AG013730 (J M ), and F32NS117784 (L D)
Publisher Copyright:
© Ko et al.
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85120899113&partnerID=8YFLogxK
U2 - 10.7554/eLife.71148
DO - 10.7554/eLife.71148
M3 - Article
C2 - 34779400
AN - SCOPUS:85120899113
SN - 2050-084X
VL - 10
JO - eLife
JF - eLife
M1 - e71148
ER -