Abstract
SummaryStudies 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.
Highlights
WldS, a spontaneous mutant mouse allele encoding a fusion protein (WLDS) with nicotinamide mononucleotide adenylyltransferase (NMNAT) activity, robustly delays injury-induced axon and synapse degeneration (Wallerian degeneration) by locally substituting for loss of the endogenous NMNAT2 isoform (Mack et al, 2001; Gilley and Coleman, 2010; Cohen et al, 2012; Conforti et al, 2014)
While the survival of NMNAT2-deficient mice homozygous for either WldS or a Sarm1 knockout allele up to 3 months of age with no overt problems initially suggested robust rescue in each case (Gilley et al, 2013, 2015), we report striking age-dependent differences between the two lines, which are likely to have important experimental and therapeutic implications
Locomotor Defects and Muscle Atrophy in Nmnat2gtE/gtE; WldS/S Mice, but Not Nmnat2gtE/gtE;Sarm1À/À Mice Mice homozygous for the Nmnat2gtE gene trap allele, lacking NMNAT2, that are homozygous for WldS or a Sarm1 knockout allele (Nmnat2gtE/gtE;WldS/S or Nmnat2gtE/gtE; Sarm1À/À mice, respectively) are born at the expected frequencies and are outwardly indistinguishable from NMNAT2-expressing littermates up to 3 months of age (Table S1) (Gilley et al, 10 Cell Reports 21, 10–16, October 3, 2017 a 2017 The Author(s)
Summary
WldS, a spontaneous mutant mouse allele encoding a fusion protein (WLDS) with nicotinamide mononucleotide adenylyltransferase (NMNAT) activity, robustly delays injury-induced axon and synapse degeneration (Wallerian degeneration) by locally substituting for loss of the endogenous NMNAT2 isoform (Mack et al, 2001; Gilley and Coleman, 2010; Cohen et al, 2012; Conforti et al, 2014). WldS has been the tool of choice for investigating the molecular basis of axon pathology in animal models of neurodegenerative diseases and has revealed an involvement of Wallerian-like mechanisms in several cases (Conforti et al, 2014). Depletion of SARM1 is, to date, the only other manipulation that can delay Wallerian degeneration and related axon degeneration in mice as robustly as exogenous expression of WLDS or other NMNAT variants (Conforti et al, 2014), but its effectiveness in maintaining the longterm health of axons and synapses in mouse models of axonopathy and/or synaptopathy has not yet been directly compared to WldS. Such a comparison is needed to ascertain the relative usefulness of Sarm deletion in determining whether Wallerianlike mechanisms are involved in models of neurodegeneration and should be informative in terms of therapeutic strategies for those disorders
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