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

Jonathan Gilley; Richard R Ribchester; Michael P Coleman

doi:10.1016/j.celrep.2017.09.027

Sarm1 Deletion, but Not Wld^S, Confers Lifelong Rescue in a Mouse Model of Severe Axonopathy

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

Authors

Jonathan Gilley¹, Richard R Ribchester², Michael P Coleman³

Affiliations

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: [email protected].
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 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.

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

MeSH terms

Animals
Armadillo Domain Proteins / antagonists & inhibitors
Armadillo Domain Proteins / deficiency
Armadillo Domain Proteins / genetics*
Axons / metabolism
Axons / pathology
Cytoskeletal Proteins / antagonists & inhibitors
Cytoskeletal Proteins / deficiency
Cytoskeletal Proteins / genetics*
Disease Models, Animal
Female
Gene Deletion
Gene Expression Regulation
Genes, Lethal*
Hindlimb / innervation
Hindlimb / metabolism
Hindlimb / pathology
Humans
Locomotion
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscular Atrophy / genetics*
Muscular Atrophy / metabolism
Muscular Atrophy / pathology
Muscular Atrophy / prevention & control
Nerve Tissue Proteins / deficiency
Nerve Tissue Proteins / genetics*
Nicotinamide-Nucleotide Adenylyltransferase / deficiency
Nicotinamide-Nucleotide Adenylyltransferase / genetics*
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
Time Factors
Wallerian Degeneration / genetics*
Wallerian Degeneration / metabolism
Wallerian Degeneration / pathology
Wallerian Degeneration / prevention & control

Substances

Armadillo Domain Proteins
Cytoskeletal Proteins
Nerve Tissue Proteins
RNA, Small Interfering
SARM1 protein, mouse
Wld protein, mouse
Nicotinamide-Nucleotide Adenylyltransferase
Nmnat2 protein, mouse

Abstract

MeSH terms

Substances

Grants and funding