Niacin-mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination.
EMBO Mol Med
; 8(12): 1438-1454, 2016 12.
Article
em En
| MEDLINE
| ID: mdl-27799291
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Complexo Vitamínico B
/
Doença de Charcot-Marie-Tooth
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Fármacos Neuroprotetores
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Proteína ADAM17
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Niacina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
EMBO Mol Med
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Itália