Journal
CELL REPORTS
Volume 21, Issue 1, Pages 10-16Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.09.027
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Funding
- Medical Research Council grants [MR/N004582/1, MR/M024075/1]
- Motor Neurone Disease Association (MNDA) grant [838-791]
- Biotechnology and Biological Sciences Research Council
- Biotechnology and Biological Sciences Research Council [BBS/E/B/000C0433] Funding Source: researchfish
- Medical Research Council [G1000702, MR/N004582/1, MR/M024075/1] Funding Source: researchfish
- Motor Neurone Disease Association [Ribchester/Apr15/838-791] Funding Source: researchfish
- BBSRC [BBS/E/B/000C0433] Funding Source: UKRI
- MRC [MR/M024075/1, G1000702, MR/N004582/1] Funding Source: UKRI
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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 WLDS-related strategies.
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