Mutations in the Microrchidia CW-Type Zinc Finger 2 (MORC2) GHKL ATPase module cause a broad range of neuropathies, such as Charcot-Marie-Tooth disease type 2Z; however, the aetiology and therapeutic strategy are not fully understood. Previously, we reported that the Morc2a p.S87L mouse model exhibited neuropathy and muscular dysfunction through DNA damage accumulation. In the present study, we analysed the gene expression of Morc2a p.S87L mice and designated the primary causing factor. We investigated the pathological pathway using Morc2a p.S87L mouse embryonic fibroblasts and human fibroblasts harbouring MORC2 p.R252W. We subsequently assessed the therapeutic effect of gene therapy administered to Morc2a p.S87L mice. This study revealed that Morc2a p.S87L causes a protein synthesis defect, resulting in the loss of function of Morc2a and high cellular apoptosis induced by high hydroxyl radical levels. We considered the Morc2a GHKL ATPase domain as a therapeutic target because it simultaneously complements hydroxyl radical scavenging and ATPase activity. We used the adeno-associated virus (AAV)-PHP.eB serotype, which has a high central nervous system transduction efficiency, to express Morc2a or Morc2a GHKL ATPase domain protein in vivo. Notably, AAV gene therapy ameliorated neuropathy and muscular dysfunction with a single treatment. Loss of functional characteristics due to protein synthesis defects in Morc2a p.S87L was also noted in human MORC2 p.S87L or p.R252W variants, indicating the correlation between mouse and human pathogenesis. In summary, CMT2Z is known as an incurable genetic disorder, but the present study demonstrated its mechanisms and treatments based on established animal models. This study demonstrates that the Morc2a p.S87L variant causes hydroxyl radical-mediated neuropathy, which can be rescued through AAV-based gene therapy.

中文翻译：

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Morc2a 变异导致羟自由基介导的神经病变，可通过恢复 GHKL ATP 酶来挽救

小睾丸 CW 型锌指 2 (MORC2) GHKL ATP 酶模块的突变可导致多种神经病，例如 2Z 型腓骨肌萎缩症；然而，其病因和治疗策略尚未完全了解。此前，我们报道了Morc2a p.S87L小鼠模型通过DNA损伤积累表现出神经病变和肌肉功能障碍。在本研究中，我们分析了 Morc2a p.S87L 小鼠的基因表达并指定了主要原因。我们使用 Morc2a p.S87L 小鼠胚胎成纤维细胞和含有 MORC2 p.R252W 的人成纤维细胞研究了病理通路。我们随后评估了对 Morc2a p.S87L 小鼠进行基因治疗的治疗效果。这项研究表明Morc2a p.S87L会导致蛋白质合成缺陷，导致Morc2a功能丧失以及高羟自由基水平诱导的高细胞凋亡。我们认为 Morc2a GHKL ATPase 结构域作为治疗靶点，因为它同时补充羟自由基清除和 ATPase 活性。我们使用具有高中枢神经系统转导效率的腺相关病毒（AAV）-PHP.eB血清型在体内表达Morc2a或Morc2a GHKL ATPase结构域蛋白。值得注意的是，AAV 基因疗法通过单一治疗即可改善神经病变和肌肉功能障碍。在人类 MORC2 p.S87L 或 p.R252W 变体中也发现了由于 Morc2a p.S87L 蛋白质合成缺陷而导致的功能特征丧失，这表明小鼠和人类发病机制之间的相关性。总之，CMT2Z 被认为是一种无法治愈的遗传性疾病，但本研究基于已建立的动物模型证明了其机制和治疗方法。这项研究表明，Morc2a p.S87L 变异会导致羟自由基介导的神经病变，这种神经病变可以通过基于 AAV 的基因治疗来挽救。