Niacin‐mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination
| العنوان: | Niacin‐mediated Tace activation ameliorates |
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| المؤلفون: | Roberta Noseda, Stefano C. Previtali, Chiara Brombin, Marta Pellegatta, Françoise Piguet, Valeria Alberizzi, Cristina Rivellini, Marta Guerrero-Valero, Alessandra Bolino, Carla Taveggia, Alessandro Nonis, Patrizia D'Adamo |
| المصدر: | EMBO Molecular Medicine |
| بيانات النشر: | EMBO, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Schwann cell, Vimentin, Charcot–Marie–Tooth neuropathies, ADAM17 Protein, Biology, Niacin, Mice, 03 medical and health sciences, Myelin, 0302 clinical medicine, Charcot-Marie-Tooth Disease, Neuregulin 1, medicine, Animals, nicotinic acid, Protein kinase B, Research Articles, Mice, Knockout, Myelin outfoldings, animal models, Disease Models, Animal, myelin, Neuroprotective Agents, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, Vitamin B Complex, Immunology, Cancer research, biology.protein, Molecular Medicine, Genetics, Gene Therapy & Genetic Disease, Signal transduction, Amyloid precursor protein secretase, 030217 neurology & neurosurgery, Research Article, Neuroscience |
| الوصف: | 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. |
| تدمد: | 1757-4684 1757-4676 |
| DOI: | 10.15252/emmm.201606349 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::030b584375e47484e50751e590187be6 https://doi.org/10.15252/emmm.201606349 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....030b584375e47484e50751e590187be6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17574684 17574676 |
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| DOI: | 10.15252/emmm.201606349 |