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.
Highlights
Axon degeneration is a hallmark of neurodegenerative disease [1], but we lack a detailed understanding of the signaling pathways that promote this destructive process in any major disorder
We have previously demonstrated that when severed in vivo, peripheral nerve axons of young Sterile Alpha and TIR Motif Containing 1 (Sarm1) knock out (Sarm1KO) mice are robustly protected against Wallerian degeneration [6]
In Sarm1KO mice, a substantial proportion of axons retained normal morphology, included being enclosed by an intact myelin sheath. Protection at this mature adult stage demonstrates that, rather than being a mechanism retained from development in young adult neurons, Sarm1-mediated axon destruction is an intrinsic characteristic of post-developmental neurons that may contribute to neurodegeneration and injury
Summary
Axon degeneration is a hallmark of neurodegenerative disease [1], but we lack a detailed understanding of the signaling pathways that promote this destructive process in any major disorder. Significant progress has been made in the characterization of molecules that regulate axon destruction after axotomy, termed Wallerian degeneration [2]. Initial molecular insights into Wallerian degeneration came from the. The WldS mutant radically changed our views on axon biology—demonstrating that axon destruction could be regulated and that under some conditions axons could suvive for long periods without a cell body
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