Journal
EMBO MOLECULAR MEDICINE
Volume 8, Issue 12, Pages 1438-1454Publisher
WILEY
DOI: 10.15252/emmm.201606349
Keywords
animal models; Charcot-Marie-Tooth neuropathies; myelin; Neuregulin 1; nicotinic acid
Categories
Funding
- Telethon-Italy [GPP10007D, GGP12017, GGP15012A, GPP10007, GGP15012, GGP12024, GPP10007B, GGP15012B]
- Association Francaise contre les Myopathies (AFM)-France [16040, 16922]
- ERA-Net for Research Programmes on Rare Diseases
- AFM-France [15-18518]
- Italian Ministry of Health [RF-2011-02347127]
- San Raffaele International Postdoctoral Programme [PCOFUND-GA-2010-267264 INVEST]
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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 -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 invivo 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.
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