Axon Biology in ALS: Mechanisms of Axon Degeneration and Prospects for Therapy

Abstract

This review addresses the longstanding debate over whether amyotrophic lateral sclerosis (ALS) is a ‘dying back’ or ‘dying forward’ disorder in the light of new gene identifications and the increased understanding of mechanisms of action for previously identified ALS genes. While the topological pattern of pathology in animal models, and more anecdotally in patients is indeed ‘dying back’, this review discusses how this fits with the fact that many of the major initiating events are thought to occur within the soma. It also discusses how widely varying ALS risk factors, including some impacting axons directly, may combine to drive a common pathway involving TAR DNA binding protein 43 (TDP-43) and neuromuscular junction (NMJ) denervation. The emerging association between sterile alpha and TIR motif-containing 1 (SARM1), a protein so far mostly associated with axon degeneration, and sporadic ALS is another major theme. The strengths and limitations of the current evidence supporting an association are considered, along with ways in which SARM1 could become activated in ALS. The final section addresses SARM1-based therapies along with the prospects for targeting other axonal steps in ALS pathogenesis.

DLK-dependent axonal mitochondrial fission drives degeneration following axotomy

“…Many clinical descriptions of axon degeneration refer to “dying back” as a pattern in which distal axons are lost before cell bodies [60, 61]. It has been suggested that dying back axon degeneration overlaps with Wallerian degeneration [62], but this remains unclear [63]. Although axon degeneration is rescued by SARM1 deletion in some models (e.g.…”

Sensory neuropathy in amyotrophic lateral sclerosis: a systematic review

“…Although data of simultaneous explorations of small and large fibers are unfortunately unavailable, literature seems to support a double pathogenetic mechanism that is quite different from small and large fibers. While in small fibers a length-dependent degeneration similar to that recognized in second motor neurons can be hypothesized [46], in large sensory fibers an acute or subacute inflammatory process could be involved.…”