Abstract
Charcot–Marie–Tooth (CMT) neuropathies are highly heterogeneous disorders caused by mutations in more than 70 genes, with no available treatment. Thus, it is difficult to envisage a single suitable treatment for all pathogenetic mechanisms. Axonal Neuregulin 1 (Nrg1) type III drives Schwann cell myelination and determines myelin thickness by ErbB2/B3‐PI3K–Akt signaling pathway activation. Nrg1 type III is inhibited by the α‐secretase Tace, which negatively regulates PNS myelination. We hypothesized that modulation of Nrg1 levels and/or secretase activity may constitute a unifying treatment strategy for CMT neuropathies with focal hypermyelination as it could restore normal levels of myelination. Here we show that in vivo delivery of Niaspan, a FDA‐approved drug known to enhance TACE activity, efficiently rescues myelination in the Mtmr2 −/− mouse, a model of CMT4B1 with myelin outfoldings, and in the Pmp22 +/− mouse, which reproduces HNPP (hereditary neuropathy with liability to pressure palsies) with tomacula. Importantly, we also found that Niaspan reduces hypermyelination of Vim (vimentin)−/− mice, characterized by increased Nrg1 type III and Akt activation, thus corroborating the hypothesis that Niaspan treatment downregulates Nrg1 type III signaling.
Highlights
Charcot–Marie–Tooth (CMT) neuropathies have a collective prevalence of 1:2,500, and as a whole represent the most common form of human hereditary neuromuscular disease
These data might suggest that the regulation of ErbB2 receptor trafficking is impaired in Mtmr2À/À Schwann cells, which in turn may result in a transient and local increase in signaling pathways relevant for PNS myelination
Neuregulin 1 (Nrg1) type III may contribute to the pathogenesis of some CMT neuropathy (Gouttenoire et al, 2013; Fledrich et al, 2014)
Summary
Charcot–Marie–Tooth (CMT) neuropathies have a collective prevalence of 1:2,500, and as a whole represent the most common form of human hereditary neuromuscular disease. CMTs are highly heterogeneous disorders commonly characterized by progressive muscular weakness, atrophy, and sensory loss (Pareyson & Marchesi, 2009; Rossor et al, 2013; Saporta & Shy, 2013). CMTs can be primarily demyelinating or axonal, at later stages both components are affected and disability parallels axonal loss. CMTs are due to mutations in at least 70 different genes, and the analyses of the underlying molecular mechanisms have revealed their highly heterogeneous pathogenesis. Given the high and increasing number of distinct CMT subtypes, it is plausible and desirable to envisage unifying therapies to treat CMT neuropathies. At present, no known therapy is available for any CMT neuropathy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
