Abstract：
Rapid nerve conduction in the peripheral nervous system (PNS) is facilitated by the multilamellar myelin sheath encasing many axons of peripheral nerves. Charcot-Marie-Tooth type 1A (CMT1A), and hereditary neuropathy with liability to pressure palsy (HNPP) are common demyelinating inherited peripheral neuropathies and are caused by mutations in the peripheral myelin protein 22 (PMP22) gene. Duplication of PMP22 leads to its overexpression and causes CMT1A, while its deletion results in PMP22 under expression and causes HNPP. Here, we investigated novel targets for modulating the protein level of PMP22 in HNPP. We found that genetic attenuation of the transcriptional coactivator Yap in Schwann cells reduces p-TAZ levels, increased TAZ activity, and increases PMP22 in peripheral nerves. Based on these findings, we ablated Yap alleles in Schwann cells of the Pmp22-haploinsufficient mouse model of HNPP and identified fewer tomacula on morphological assessment and improved nerve conduction in peripheral nerves. These findings suggest YAP modulation may be a new avenue for treatment of HNPP.
摘要：
周围神经系统（PNS）中的快速神经传导是由包裹许多周围神经轴突的多层髓鞘促进的。Charcot-Marie-Tooth1A型(CMT1A),和遗传性神经病伴压力性麻痹（HNPP）是常见的脱髓鞘遗传性外周神经病，由外周髓鞘蛋白22（PMP22）基因突变引起。复制PMP22导致其过表达并导致CMT1A，而其缺失导致PMP22低表达并引起HNPP。这里,我们研究了调节HNPP中PMP22蛋白水平的新靶点。我们发现施万细胞中转录共激活因子Yap的遗传衰减降低了p-TAZ水平，TAZ活性增加，并增加周围神经中的PMP22。基于这些发现,我们在HNPP的Pmp22单倍体不足小鼠模型的施万细胞中消融了Yap等位基因，并在形态学评估和改善周围神经的神经传导方面鉴定了较少的番茄。这些发现表明YAP调节可能是治疗HNPP的新途径。
