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

03 Nov 2017

Studies with the WldS 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 WldS, but their relative capacities to confer long-term protection against related, non-injury axonopathy and/or synaptopathy have not been directly compared. Whilst Sarm1 deletion or WldS can each rescue perinatal lethality and widespread Wallerian-like axonopathy in young NMNAT2-deficient mice, we now report that an absence of SARM1 enables these mice to survive into old age with no overt phenotype whereas those rescued by WldS 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 WldS for investigating Wallerian-like mechanisms in disease models and suggest that SARM1 blockade may have greater therapeutic potential than WLDS-related strategies.