Niacin-mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination.
Alessandra BolinoFrançoise PiguetValeria AlberizziMarta PellegattaCristina RivelliniMarta Guerrero-ValeroRoberta NosedaChiara BrombinAlessandro NonisPatrizia D'AdamoCarla TaveggiaStefano Carlo PrevitaliPublished in: EMBO molecular medicine (2016)
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.
Keyphrases
- type iii
- signaling pathway
- pi k akt
- cell proliferation
- stem cells
- metabolic syndrome
- type diabetes
- single cell
- skeletal muscle
- combination therapy
- epithelial mesenchymal transition
- insulin resistance
- spinal cord injury
- mesenchymal stem cells
- mouse model
- transcription factor
- genome wide
- induced apoptosis
- smoking cessation
- tyrosine kinase