Sarm1 Deletion, but Not WldS, Confers Lifelong Rescue in a Mouse Model of Severe Axonopathy

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): Jonathan Gilley, Richard R. Ribchester, Michael P. Coleman
Studies with the Wld^S mutant mouse have shown that axon and synapse pathology in several models of neurodegenerative diseases are mechanistically related to injury-induced axon degeneration (Wallerian degeneration). Crucially, an absence of SARM1 delays Wallerian degeneration as robustly as Wld^S, but their relative capacities to confer long-term protection against related, non-injury axonopathy and/or synaptopathy have not been directly compared. While Sarm1 deletion or Wld^S can rescue perinatal lethality and widespread Wallerian-like axonopathy in young NMNAT2-deficient mice, we report that an absence of SARM1 enables these mice to survive into old age with no overt phenotype, whereas those rescued by Wld^S invariantly develop a progressive neuromuscular defect in their hindlimbs from around 3 months of age. We therefore propose Sarm1 deletion as a more reliable tool than Wld^S for investigating Wallerian-like mechanisms in disease models and suggest that SARM1 blockade may have greater therapeutic potential than WLD^S-related strategies.

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Both Sarm1 deletion and Wld^S prevent axonopathy and perinatal lethality in NMNAT2-deficient mice. Gilley et al. report that those rescued by Wld^S develop hindlimb motor problems as young adults, whereas Sarm1 deletion allows survival to 24 months with no overt defect. These findings have important analytical and therapeutic implications.


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