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Cell Rep. 2017 Oct 3;21(1):10-16. doi: 10.1016/j.celrep.2017.09.027.

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

Author information

1
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK; Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK. Electronic address: jg792@cam.ac.uk.
2
Biomedical Sciences, Euan MacDonald Centre for MND Research and Centre for Discovery Brain Sciences, The University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, UK.
3
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK; Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.

Abstract

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. While Sarm1 deletion or WldS 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 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.

KEYWORDS:

NMNAT2-deficient mice; Sarm1; Wld(S); aging; axonopathy; disease model; motor function; neurodegeneration; neuromuscular junction; synaptopathy

PMID:
28978465
PMCID:
PMC5640801
DOI:
10.1016/j.celrep.2017.09.027
[Indexed for MEDLINE]
Free PMC Article

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