![]() ![]() ![]() One subtype of the disease-Charcot-Marie-Tooth 2B-is caused by mutations in a gene called rab7, which codes for a protein that helps to regulate the breakdown of waste proteins inside cells.Ĭharcot-Marie-Tooth 2B is described as a genetically dominant disorder because all patients have one wild type copy and one mutant copy of the rab7 gene. ![]() The sensory and motor nerves gradually degenerate, causing muscles to waste away and leading to the loss of touch sensation across the body. Our results suggest a therapeutic approach opposite to the currently proposed reduction of mutant protein function.Ĭharcot-Marie-Tooth disease is an inherited disorder of the nervous system with symptoms that typically begin in adolescence or early adulthood. Instead, they indicate a dosage-dependent sensitivity of neurons to rab7-dependent degradation. These findings are not consistent with a gain-of-function mechanism. Live imaging reveals that CMT2B proteins are inefficiently recruited to endosomes, but do not impair endosomal maturation. Consequently, expression of CMT2B mutants at levels between 0.5 and 10-fold their endogenous levels fully rescues the neuropathy-like phenotypes of the rab7 mutant. All CMT2B mutant proteins retain 10–50% function based on quantitative imaging, electrophysiology, and rescue experiments in sensory and motor neurons in vivo. Here we show that loss of rab7, but not overexpression of rab7 CMT2B mutants, causes adult-onset neurodegeneration in a Drosophila model. Mutations in rab7 are thought to cause the dominant neuropathy Charcot-Marie-Tooth 2B (CMT2B) by a gain-of-function mechanism. Our data show that cemdomespib therapy improves CMTX1-linked neuropathy in an Hsp70-dependent but a c-jun-independent manner and without regard to the nature of the underlying Cx32 mutation.The small GTPase Rab7 is a key regulator of endosomal maturation in eukaryotic cells. While the deletion of c-jun worsened the neuropathy, cemdomespib therapy remained effective in improving MNCV and grip strength. To determine if c-jun may be downstream of Hsp70 and necessary for drug efficacy, c-jun expression was specifically deleted in Schwann cells of Cx32def mice. Five months of novologue therapy was associated with improved neuromuscular junction morphology, femoral motor nerve myelination, reduction in foamy macrophages, and a decrease in Schwann cell c-jun levels. Drug efficacy required Hsp70 as improvements in MNCV, and the grip strength was abrogated in Cx32def × Hsp70 knockout mice. Daily drug therapy significantly improved motor nerve conduction velocity (MNCV) and grip strength in all three models, but the compound muscle action potential was only improved in Cx32def mice. We examined if 1 to 5 months of daily cemdomespib therapy may improve neuropathic symptoms in three mouse models of CMTX1 (Cx32 deficient (Cx32def), T55I-Cx32def, and R75W-Cx32 mice). Cemdomespib is an orally bioavailable novologue that manifests neuroprotective activity by modulating the expression of heat shock protein 70 (Hsp70). CMTX1 currently lacks a pharmacologic approach toward disease management, and we have previously shown that modulating the expression of molecular chaperones using novologue therapy may provide a viable disease-modifying approach to treat metabolic and demyelinating neuropathies. Charcot-Marie-Tooth X1 (CMTX1) disease is an inherited peripheral neuropathy that arises from loss-of-function mutations in the protein connexin 32 (Cx32). ![]()
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