Axonal degeneration in peripheral neuropathies : from the molecular mechanisms to the therapeutic approach

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy, affecting approximately 1 in 2,500 people. It is genetically heterogeneous, with mutations in over 100 genes, and affects both motor and sensory nerves. The T124M mutation in the MPZ gene causes CMT2J, an interesting subtype with a high prevalence in northern Italy. Although MPZ is exclusively expressed in peripheral myelin, CMT2J is characterized by axonal degeneration with only minimal myelin involvement. This work presents a detailed characterization of the recently described MpzT124M mouse model. As previously reported, we confirmed extensive axonal degeneration and fibre loss in peripheral nerves. Given the role of SARM1 in mediating Wallerian degeneration, we crossed MpzT124M mice with Sarm1 null mice to investigate whether SARM1 deletion could attenuate axonal degeneration. While SARM1 deletion did not significantly rescue electrophysiological deficits, it partially reduced degenerative features in sciatic nerves, preserved axonal integrity in motor-dominant femoral nerves and decreased neurofilament light chain (NfL) levels in plasma. These findings indicate that SARM1 modulation may offer selective protection in CMT2J, depending on nerve type and structure. Proteomic profiling of MpzT124M sciatic nerves revealed downregulation of key axonal transport proteins, including kinesins and dynactin. We then observed a progressive decrease in acetylation of α-tubulin, indicative of compromised microtubule stability. In vivo imaging confirmed the impaired axonal transport in MpzT124M mice, with reduced retrograde transport speed and increased pausing of endosomes. Based on these findings, we investigated HDAC6, a deacetylase that regulates α-tubulin acetylation and microtubule stability. Crossing MpzT124M mice with Hdac6 null mice demonstrated that Hdac6 deletion restored α-tubulin acetylation levels, normalized endosomal transport dynamics, and improved motor function. Morphological assessments showed reduced signs of axonal degeneration and improved nerve integrity, suggesting that HDAC6 inhibition could stabilize axonal structure and improve transport efficiency in CMT2J. Overall, our work identifies distinct roles for SARM1 and HDAC6 in the pathophysiology of CMT2J. Although they act via different pathways, both may represent viable therapeutic targets. Given that HDAC6 inhibitors are already available, testing them in MpzT124M mice would be a logical next step. However, the late disease onset and slow progression in this model make in vivo drug screening time- and resource-intensive. To overcome this limitation, we are developing a human iPSC-derived neuromuscular assembloid model carrying the T124M MPZ mutation. These cultures include motor neurons, Schwann cells and muscle cells and would provide a human relevant in vitro model for CMT2J.