dSarm/Sarm1 Is Required for Activation of an Injury-Induced Axon Death Pathway
By Jeannette M. Osterloh, Jing Yang, T. Rooney, A. Fox, R. Adalbert, Eric H. Powell, Amy E Sheehan, M. Avery, R. Hackett, Mary A. Logan and 12 more. Science, 2012
663 citations recorded by the source corpus.
Sarm-Assisted Suicide Neurodegenerative disease or nerve lesions cause axons and synapses to disintegrate through a process known as Wallerian degeneration, which may involve an active “axon death program.” Osterloh et al. (p. 481, published online 7 June; see the Perspective by Yu and Luo) identify loss-of-function mutations in Drosophila dSarm that are capable of blocking the degeneration of severed axons for the fly life span. Deletion of mouse Sarm1 provides similar protection to severed axons for weeks after injury, which suggests that Sarm is part of an ancient axonal death signaling cascade. Mutations in a scaffold protein block the Wallerian degeneration of axons in flies and mice. Axonal and synaptic degeneration is a hallmark of peripheral neuropathy, brain injury, and neurodegenerative disease. Axonal degeneration has been proposed to be mediated by an active autodestruction program, akin to apoptotic cell death; however, loss-of-function mutations capable of potently blocking axon self-destruction have not been described. Here, we show that loss of the Drosophila Toll receptor adaptor dSarm (sterile α/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously suppresses Wallerian degeneration for weeks after axotomy. Severed mouse Sarm1 null axons exhibit remarkable long-term survival both in vivo and in vitro, indicating that Sarm1 prodegenerative signaling is conserved in mammals. Our results provide direct evidence that axons actively promote their own destruction after injury and identify dSarm/Sarm1 as a member of an ancient axon death signaling pathway.
Subfields: Aging, Cellular and Molecular Neuroscience
View Paper: https://www.semanticscholar.org/paper/7df6554b0e6fd634fdaa15ac9ef3b176e440bb3c
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Citations in the corpus
- NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “Axons require the NADase activity of the full length SARM1 to facilitate axonal degeneration and NAD consumption after injury.(33,34,485) Similarly, the loss of endogenous NMNAT2 is an important cause of axon degeneration after injury.”
- Therapeutic potential of NAD-boosting molecules: the in vivo evidence (2018, neutral): “SARM1 is a newly discovered NAD+ cleavage enzyme in neurons and possibly other cell types (Conforti et al., 2014; Essuman et al., 2017; Gerdts et al., 2013; Osterloh et al., 2012).”