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. 2018 Nov 1;27(21):3761-3771.
doi: 10.1093/hmg/ddy260.

Loss of Sarm1 does not suppress motor neuron degeneration in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Owen M Peters  1   2 , Elizabeth A Lewis  1 , Jeannette M Osterloh  1 , Alexandra Weiss  2 , Johnny S Salameh  2 , Jake Metterville  2 , Robert H Brown  2 , Marc R Freeman  1
Affiliations

Loss of Sarm1 does not suppress motor neuron degeneration in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Owen M Peters et al. Hum Mol Genet. .

Abstract

Axon degeneration occurs in all neurodegenerative diseases, but the molecular pathways regulating axon destruction during neurodegeneration are poorly understood. Sterile Alpha and TIR Motif Containing 1 (Sarm1) is an essential component of the prodegenerative pathway driving axon degeneration after axotomy and represents an appealing target for therapeutic intervention in neurological conditions involving axon loss. Amyotrophic lateral sclerosis (ALS) is characterized by rapid, progressive motor neuron degeneration and muscle atrophy, causing paralysis and death. Patient tissue and animal models of ALS show destruction of upper and lower motor neuron cell bodies and loss of their associated axons. Here, we investigate whether loss of Sarm1 can mitigate motor neuron degeneration in the SOD1G93A mouse model of ALS. We found no change in survival, behavioral, electrophysiogical or histopathological outcomes in SOD1G93A mice null for Sarm1. Blocking Sarm1-mediated axon destruction alone is therefore not sufficient to suppress SOD1G93A-induced neurodegeneration. Our data suggest the molecular pathways driving axon loss in ALS may be Sarm1-independent or involve genetic pathways that act in a redundant fashion with Sarm1.

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Figures

Figure 1
Figure 1
Sarm1-mediated axon destruction can be suppressed in aged mice and is not altered by transgenic expression of mutant SOD1. (A) Representative micrographs showing toluidine blue-stained intact or axotomized sciatic nerves of 1-year-old wild-type Sarm1KO mice. Morphologically intact axons were widespread in the distal sciatic nerve 14-day post-lesion in Sarm1KO mice. (B) Representative images of intact or axotomized sciatic nerve of 5-week-old control and SOD1G93A transgenic mice 14 days post-axotomy, showing preservation of axons in SarmKO mice. Scale bar = 20 μm.
Figure 2
Figure 2
Sarm1 does not contribute to onset, survival or sensorimotor performance deficits in SOD1G93A mice. Percentage of transgenic colony free of (A) hind limb tremor and (B) hind limb paralysis. (C) Kaplan–Meyer plot showing survival of transgenic cohorts (A–C: Sarm1Het SOD1G93A, n = 37; Sarm1KO SOD1G93A, n = 44; Sarm1Het control, n = 31; Sarm1KO control, n = 27; Sarm1Het SOD1G93A vs Sarm1KO SOD1G93A; Log-Rank test, P-value > 0.05). (D) Fall latency of male transgenic mice on 4–40 rpm accelerating rotarod task for assessment of sensorimotor function (SOD1G93A groups, n = 20; control groups, n = 15; two-way ANOVA with Bonferonni post-hoc test).
Figure 3
Figure 3
Deficits in neuromuscular electrophysiological function associated with SOD1G93A expression are not ameliorated in mice lacking Sarm1. Neuromuscular electrophysiological function was tested in SOD1G93A and control mice of Sarm1WT (black), Sarm1Het (blue) or Sarm1KO (red) genotype. Assessing the gastrocnemius muscle of p120–130 mice for (A) MUNE, (B) motor unit size and (C) CMAP failed to show any significant difference in phenotype between SOD1G93A transgenic groups (mean ±  SEM, n = 4–14; two-way ANOVA with Bonferonni post-hoc test; ns = non-significant; **P-value < 0.01; ***P-value < 0.001).
Figure 4
Figure 4
Progressive loss of myelinated motor axons is not ameliorated by loss of Sarm1. Total number of myelinated axons in the L5 ventral nerve root of SOD1G93A transgenic mice wild type, heterozygous-null or homozygous-null for Sarm1 at (A) p80–90, (B) p120–130 and (C) end stage (n = 3–11, mean ± SEM; A and B, one-way ANOVA; C, Student t test). Frequency distribution of axon diameters at (A′) p90, (B′) p120 and (C′) endpoint expressed as percentage of total axons measured (mean ± SEM, two-way ANOVA with Bonferonni post-hoc test, *P-value < 0.05, **P-value < 0.01). (D) Representative images of L5 ventral nerve root myelinated axons at p120 in SOD1G93A mice wild-type, heterozygous-null or homozygous-null for Sarm1 with comparison images from littermate controls not expressing SOD1G93A (scale bar = 20 μm).
Figure 5
Figure 5
Sarm1 does not contribute to NMJ denervation in SOD1G93A transgenic mice. (A) Representative images of immunofluorescent staining of NMJs in the gastrocnemius muscle at p120–130. (Green = synaptophysin and beta-III-tubulin co-stain, Red = alpha-bungarotoxin, scale bar = 50 μm) (B) Percentage of innervated NMJs in the gastrocnemius muscles of transgenic cohorts at p120–130 (mean ± SEM, n = 3–5, two-way ANOVA with Bonferonni post-hoc test, *P-value < 0.05, **P-value < 0.01, ***P-value < 0.001).
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