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

13 Citations (Scopus)

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

Fingerprint

Neuregulin-1
Niacin
Amyloid Precursor Protein Secretases
Myelin Sheath
Schwann Cells
Vimentin
Down-Regulation
Mutation
Pharmaceutical Preparations
Genes

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Niacin-mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination. / Bolino, Alessandra; Piguet, Françoise; Alberizzi, Valeria; Pellegatta, Marta; Rivellini, Cristina; Guerrero-Valero, Marta; Noseda, Roberta; Brombin, Chiara; Nonis, Alessandro; D'Adamo, Patrizia; Taveggia, Carla; Previtali, Stefano.

In: EMBO Molecular Medicine, Vol. 8, No. 12, 01.12.2016, p. 1438-1454.

Research output: Contribution to journalArticle

Bolino, A, Piguet, F, Alberizzi, V, Pellegatta, M, Rivellini, C, Guerrero-Valero, M, Noseda, R, Brombin, C, Nonis, A, D'Adamo, P, Taveggia, C & Previtali, S 2016, 'Niacin-mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination', EMBO Molecular Medicine, vol. 8, no. 12, pp. 1438-1454. https://doi.org/10.15252/emmm.201606349
Bolino A, Piguet F, Alberizzi V, Pellegatta M, Rivellini C, Guerrero-Valero M et al. Niacin-mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination. EMBO Molecular Medicine. 2016 Dec 1;8(12):1438-1454. https://doi.org/10.15252/emmm.201606349
Bolino, Alessandra ; Piguet, Françoise ; Alberizzi, Valeria ; Pellegatta, Marta ; Rivellini, Cristina ; Guerrero-Valero, Marta ; Noseda, Roberta ; Brombin, Chiara ; Nonis, Alessandro ; D'Adamo, Patrizia ; Taveggia, Carla ; Previtali, Stefano. / Niacin-mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination. In: EMBO Molecular Medicine. 2016 ; Vol. 8, No. 12. pp. 1438-1454.
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