Charcot-Marie-Tooth X1 (CMTX1) disease is an inherited
peripheral
neuropathy that arises from loss-of-function mutations in the protein
connexin 32 (Cx32). 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. Cemdomespib is an orally bioavailable
novologue that manifests neuroprotective activity by modulating the
expression of heat shock protein 70 (Hsp70). 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). 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. Drug efficacy required Hsp70 as improvements in MNCV, and the
grip strength was abrogated in Cx32def × Hsp70 knockout 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. 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. While the deletion of c-jun worsened the neuropathy,
cemdomespib therapy remained effective in improving MNCV and grip
strength. 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.