Kim Ji Won, Nam Soo Hyun, Lee Geon Seong, Chung Hye Yoon, Kim Eun Young, Han Jeong Pil, Jang Jae-Hyung, Choi Byung-Ok, Yeom Su Cheong
Graduate School of International Agricultural Technology and Institute of Green BioScience and Technology, Seoul National University, 1447 Pyeongchang-Ro, Daewha, Pyeongchang, 25354, Gangwon, Korea.
Cell & Gene Therapy Institute, Samsung Medical Center, Seoul, 06351, Korea.
Acta Neuropathol. 2025 Aug 4;150(1):13. doi: 10.1007/s00401-025-02922-2.
Charcot-Marie-Tooth disease type 2Z (CMT2Z) is an inherited axonal neuropathy caused by haploinsufficiency of microrchidia CW-type zinc finger protein 2 (MORC2), which leads to elevated hydroxyl radical levels, reduced ATPase activity, and apoptosis-mediated neuromuscular degeneration. CMT2Z presents with severe clinical manifestations, yet no widely applicable and affordable treatment has been developed. While gene therapy presents a theoretical solution, its feasibility remains constrained by prohibitive costs and delivery challenges. We observed sex-specific differences in muscle function in a CMT2Z mouse model carrying the microrchidia CW-type zinc finger protein 2A (Morc2a) p.S87L variant, with males exhibiting more severe weakness, suggesting a protective role of estradiol in females. Thus, we hypothesized that identifying and utilizing this factor could contribute to CMT2Z drug development. We found that estradiol stabilizes the Morc2a variant protein by inhibiting autophagy, independently of specific estrogen receptors, thereby mitigating hydroxyl radical-induced mitochondrial aggregation and apoptosis while restoring ATPase function. Subcutaneous implantation of estradiol pellets in the CMT2Z mouse model significantly improved Morc2a protein stability in the quadriceps femoris and sciatic nerve, reversed mitochondrial aggregation, and ameliorated both muscular and peripheral nerve degeneration. Notably, symptomatic Morc2a p.S87L mice exhibited robust peripheral nerve regeneration, demonstrating estradiol's ability to restore function rather than merely delay disease progression. Moreover, the therapeutic effects were reproduced in human MORC2 p.R252W variants, further confirming its translational potential. As an FDA-approved compound with well-characterized pharmacokinetics, estradiol represents a rapidly deployable strategy for treating CMT2Z. This study highlights the pivotal role of oxidative stress in the pathophysiology of CMT2Z and identifies MORC2 stabilization as a promising intervention. Moreover, the findings advocate for repurposing existing therapeutics to address rare genetic disorders, broadening treatment paradigms for neuromuscular diseases beyond CMT2Z.
2Z型夏科-马里-图斯病（CMT2Z）是一种遗传性轴索性神经病，由小睾丸CW型锌指蛋白2（MORC2）单倍体不足引起，导致羟自由基水平升高、ATP酶活性降低以及凋亡介导的神经肌肉变性。CMT2Z临床表现严重，但尚未开发出广泛适用且负担得起的治疗方法。虽然基因治疗提供了一种理论解决方案，但其可行性仍受到高昂成本和递送挑战的限制。我们在携带小睾丸CW型锌指蛋白2A（Morc2a）p.S87L变体的CMT2Z小鼠模型中观察到肌肉功能的性别差异，雄性表现出更严重的肌无力，提示雌二醇对雌性有保护作用。因此，我们假设识别和利用这一因素可能有助于CMT2Z的药物开发。我们发现，雌二醇通过抑制自噬来稳定Morc2a变体蛋白，独立于特定雌激素受体，从而减轻羟自由基诱导的线粒体聚集和凋亡，同时恢复ATP酶功能。在CMT2Z小鼠模型中皮下植入雌二醇微丸可显著提高股四头肌和坐骨神经中Morc2a蛋白的稳定性，逆转线粒体聚集，并改善肌肉和周围神经变性。值得注意的是，有症状的Morc2a p.S87L小鼠表现出强大的周围神经再生能力，证明雌二醇能够恢复功能而非仅仅延缓疾病进展。此外，在人类MORC2 p.R252W变体中也再现了治疗效果，进一步证实了其转化潜力。作为一种具有明确药代动力学特征且已获美国食品药品监督管理局批准的化合物，雌二醇代表了一种可快速应用于治疗CMT2Z的策略。本研究强调了氧化应激在CMT2Z病理生理学中的关键作用，并确定MORC2稳定化是一种有前景的干预措施。此外，研究结果提倡重新利用现有疗法来治疗罕见遗传病，拓宽CMT2Z以外神经肌肉疾病的治疗模式。
