Niacin-mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination.
Niacin-mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination.
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DOI：
10.15252/emmm.201606349
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发表时间：
2016-12
影响因子：
11.1
通讯作者：
Previtali SC
中科院分区：
文献类型：
--
作者：
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 SC
Charcot-Marie-Tooth（CMT）神经病变是由70多个基因突变引起的高度异质性疾病，目前尚无可用的治疗方法。因此，很难设想针对所有发病机制的单一合适治疗。轴突神经调节蛋白1（Nrg 1）III型通过ErbB 2/B3-PI 3 K-Akt信号通路激活驱动许旺细胞髓鞘形成并决定髓鞘厚度。Nrg 1 III型受α-分泌酶Tace抑制，其负调节PNS髓鞘形成。我们假设Nrg 1水平和/或分泌酶活性的调节可能构成CMT神经病与局灶性髓鞘形成过度的统一治疗策略，因为它可以恢复正常的髓鞘形成水平。在这里，我们表明，体内递送Niaspan（一种FDA批准的药物，已知可增强TACE活性）可有效地挽救Mtmr 2 −/−小鼠（一种具有髓鞘外折叠的CMT 4 B1模型）和Pmp 22 +/−小鼠（用tomacula复制HNPP（易患压力麻痹的遗传性神经病））的髓鞘形成。重要的是，我们还发现Niaspan减少了Vim（波形蛋白）−/−小鼠的髓鞘过度形成，其特征在于增加了Nrg 1 III型和Akt活化，从而证实了Niaspan治疗下调Nrg 1 III型信号传导的假设。
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.