title: Niacin-mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination.
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.
authors: INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy bolino.alessandra@hsr.it.|Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Alessandra
authors: 0000-0002-8980-4878
authors: A
authors: Bolino
authors: INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.|Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Françoise
authors: F
authors: Piguet
authors: INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.|Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Valeria
authors: V
authors: Alberizzi
authors: INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.|Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Marta
authors: M
authors: Pellegatta
authors: INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.|Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Cristina
authors: C
authors: Rivellini
authors: INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.|Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Marta
authors: M
authors: Guerrero-Valero
authors: INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.|Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Roberta
authors: R
authors: Noseda
authors: University Centre of Statistics in the Biomedical Sciences (CUSSB), Vita-Salute San Raffaele University, Milan, Italy.
authors: Chiara
authors: C
authors: Brombin
authors: University Centre of Statistics in the Biomedical Sciences (CUSSB), Vita-Salute San Raffaele University, Milan, Italy.
authors: Alessandro
authors: A
authors: Nonis
authors: Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Patrizia
authors: P
authors: D'Adamo
authors: INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.|Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Carla
authors: C
authors: Taveggia
authors: INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.|Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.|Department of Neurology, San Raffaele Scientific Institute, Milan, Italy.
authors: Stefano Carlo
authors: SC
authors: Previtali
mesh_terms: D000072198:ADAM17 Protein / Q000378:metabolism*; D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy* / Q000473:pathology*; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009525:Niacin / Q000008:administration & dosage*; D016896:Treatment Outcome; D014803:Vitamin B Complex / Q000008:administration & dosage*
chemical_list: D018696:Neuroprotective Agents; D014803:Vitamin B Complex; D009525:Niacin; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
keywords: Charcot–Marie–Tooth neuropathies; Neuregulin 1; animal models; myelin; nicotinic acid