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Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of cancer treatment, often associated with degeneration of sensory axons or their terminal regions. Presence of the slow Wallerian degeneration protein (WLD S ), or genetic deletion of sterile alpha and TIR motif containing protein 1 (SARM1), which strongly protect axons from degeneration after injury or axonal transport block, alleviate pain in several CIPN models. However, oxaliplatin can cause an acute pain response, suggesting a different mechanism of pain generation. Here, we tested whether the presence of WLD S or absence of SARM1 protects against acute oxaliplatin-induced pain in mice after a single oxaliplatin injection. In BL/6 and Wld S mice, oxaliplatin induced significant mechanical and cold hypersensitivities which were absent in Sarm1 -/- mice. Despite the presence of hypersensitivity there was no significant loss of intraepidermal nerve fibers (IENFs) in the footpads of any mice after oxaliplatin treatment, suggesting that early stages of pain hypersensitivity could be independent of axon degeneration. To identify other changes that could underlie the pain response, RNA sequencing was carried out in DRGs from treated and control mice of each genotype. Sarm1 -/- mice had fewer gene expression changes than either BL/6 or Wld S mice. This is consistent with the pain measurements in demonstrating that Sarm1 -/ - DRGs remain relatively unchanged after oxaliplatin treatment, unlike those in BL/6 and Wld S mice. Changes in levels of four transcripts - Alas2, Hba-a1, Hba-a2, and Tfrc - correlated with oxaliplatin-induced pain, or absence thereof, across the three genotypes. Our findings suggest that targeting SARM1 could be a viable therapeutic approach to prevent oxaliplatin-induced acute neuropathic pain., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Wallerian degeneration slow (Wld(S)) mice express a chimeric protein that delays axonal degeneration. The N-terminal domain (N70), which is essential for axonal protection in vivo, binds valosin-containing protein (VCP) and targets both Wld(S) and VCP to discrete nuclear foci. We characterized the formation, composition and localization of these potentially important foci. Missense mutations show that the N-terminal sixteen residues (N16) of Wld(S) are essential for both VCP binding and targeting Wld(S) to nuclear foci. Removing N16 abolishes foci, and VCP binding sequences from ataxin-3 or HrdI restore them. In vitro, these puncta co-localize with proteasome subunits. In vivo, Wld(S) assumes a range of nuclear distribution patterns, including puncta, and its neuronal expression and intranuclear distribution is region-specific and varies between spontaneous and transgenic Wld(S) models. We conclude that VCP influences Wld(S) intracellular distribution, and thus potentially its function, by binding within the N70 domain required for axon protection.

The "slow Wallerian degeneration" (Wld(S)) gene is neuroprotective in numerous models of axonal degeneration. Axonal degeneration is an early feature of disease progression in the SOD1G93A mouse, a widely used model of familial amyotrophic lateral sclerosis (fALS). We crossed the Wld(S) mouse with the SOD1G93A mouse to investigate whether the Wld(S) gene could prolong survival and modify neuropathology in these mice. SOD/Wld(S) mice showed levels of motor axon loss similar to that seen in SOD1G93A mice. The presence of the Wld(S) gene, however, modestly prolonged survival and delayed denervation at the neuromuscular junction. Prolonged survival was more prominent in female mice and did not depend on whether animals were heterozygous or homozygous for the Wld(S) gene. We also report that SOD1G93A mice show significant degeneration of sensory axons during the course of disease, supporting previous data from humans demonstrating that ALS is not purely a motor disorder.