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.

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.

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