Department of Cell & Developmental Biology, School of Medicine Basic Sciences, Vanderbilt University, Nashville, Tennessee, United States of America.
Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2023 Oct 4;18(10):e0292086. doi: 10.1371/journal.pone.0292086. eCollection 2023.
Tuberous Sclerosis Complex (TSC) is a debilitating developmental disorder characterized by a variety of clinical manifestations. TSC is caused by mutations in the TSC1 or TSC2 genes, which encode the hamartin/tuberin proteins respectively. These proteins function as a heterodimer that negatively regulates the mechanistic Target of Rapamycin Complex 1 (mTORC1). TSC research has focused on the effects of mTORC1, a critical signaling hub, on regulation of diverse cell processes including metabolism, cell growth, translation, and neurogenesis. However, non-canonical functions of TSC2 are not well studied, and the potential disease-relevant biological mechanisms of mutations affecting these functions are not well understood. We observed aberrant multipolar mitotic division, a novel phenotype, in TSC2 mutant iPSCs. The multipolar phenotype is not meaningfully affected by treatment with the inhibitor rapamycin. We further observed dominant negative activity of the mutant form of TSC2 in producing the multipolar division phenotype. These data expand the knowledge of TSC2 function and pathophysiology which will be highly relevant to future treatments for patients with TSC.
结节性硬化症（TSC）是一种使人虚弱的发育障碍，其特征是多种临床表现。TSC 是由 TSC1 或 TSC2 基因突变引起的，这两个基因分别编码错构瘤蛋白/结节素蛋白。这些蛋白作为异二聚体起作用，负调控雷帕霉素靶蛋白复合物 1（mTORC1）。TSC 研究集中在 mTORC1（一个关键的信号枢纽）对代谢、细胞生长、翻译和神经发生等多种细胞过程的调节作用。然而，TSC2 的非典型功能尚未得到很好的研究，影响这些功能的突变的潜在疾病相关生物学机制也尚未得到很好的理解。我们在 TSC2 突变的 iPSC 中观察到了异常的多极有丝分裂分裂，这是一种新的表型。多极表型不受雷帕霉素抑制剂治疗的显著影响。我们进一步观察到 TSC2 突变形式的显性负性活性在产生多极分裂表型方面的作用。这些数据扩展了 TSC2 功能和病理生理学的知识，这将对 TSC 患者的未来治疗具有重要意义。
