Niacin-mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination

Alessandra Bolino, Françoise Piguet, Valeria Alberizzi, Marta Pellegatta, Cristina Rivellini, Marta Guerrero-Valero, Roberta Noseda, Chiara Brombin, Alessandro Nonis, Patrizia D'Adamo, Carla Taveggia, Stefano Previtali

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1438-1454
Number of pages17
JournalEMBO Molecular Medicine
Volume8
Issue number12
DOIs
Publication statusPublished - Dec 1 2016

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Keywords

  • animal models
  • Charcot–Marie–Tooth neuropathies
  • myelin
  • Neuregulin 1
  • nicotinic acid

ASJC Scopus subject areas

  • Molecular Medicine

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