Buttermore Elizabeth D, Srinivasan Gayathri Rajaram, Jumo Hellen, Swanson Amanda C, O'Kelly Benjamin, Makhortova Nina R, Sahin Mustafa, Tzannis Stelios T
Human Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA, United States.
F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, United States.
Front Neurosci. 2025 Jul 28;19:1595880. doi: 10.3389/fnins.2025.1595880. eCollection 2025.
The mechanistic target of rapamycin (mTOR) pathway plays an important role in regulating multiple cellular processes, including cell growth, autophagy, proliferation, protein synthesis, and lipid synthesis, among others. Given the central role of this pathway in multiple cellular processes, it is not surprising that mTOR pathway dysregulation is a key mechanism underlying several neurological disorders, including Tuberous Sclerosis Complex (TSC). TSC patients typically present with pathogenic variants in the or genes, which encode proteins forming a complex that plays an important role in modulating mTOR activity. We previously reported cellular and functional deficits in induced pluripotent stem cell (iPSC)-derived neurons from TSC patients. These deficits were reversed by inhibiting mTOR activity using rapamycin treatment, revealing the role of mTOR signaling in the regulation of cell morphology and hyperexcitability phenotypes in TSC patient-derived neurons. However, chronic rapamycin treatment inhibits both mTORC1 and mTORC2 activity and its clinical use is associated with significant side effects. With the development of novel mTORC1-selective compounds, we aimed to assess whether selective inhibition of mTORC1 likewise reversed the cellular and functional deficits found in TSC patient-derived neurons. Our results indicate that the novel, selective mTORC1 inhibitors nearly fully reversed the cellular and functional deficits of iPSC-derived neurons in a fashion and magnitude similar to rapamycin, as they all reversed and near-normalized their neuronal hyperexcitability and abnormal morphology as compared to the DMSO-treated cells. These data suggest that mTORC1-specific compounds could provide clinical therapeutic benefit similar to rapamycin without the same side effects.
雷帕霉素的作用机制靶点（mTOR）通路在调节多种细胞过程中发挥着重要作用，包括细胞生长、自噬、增殖、蛋白质合成和脂质合成等。鉴于该通路在多种细胞过程中的核心作用，mTOR通路失调是包括结节性硬化症（TSC）在内的几种神经系统疾病的关键机制也就不足为奇了。TSC患者通常在 或 基因中存在致病变异，这些基因编码形成复合物的蛋白质，该复合物在调节mTOR活性中起重要作用。我们之前报道了TSC患者诱导多能干细胞（iPSC）衍生神经元中的细胞和功能缺陷。使用雷帕霉素治疗抑制mTOR活性可逆转这些缺陷，揭示了mTOR信号在调节TSC患者衍生神经元的细胞形态和过度兴奋表型中的作用。然而，长期雷帕霉素治疗会抑制mTORC1和mTORC2活性，并且其临床应用与显著的副作用相关。随着新型mTORC1选择性化合物的开发，我们旨在评估选择性抑制mTORC1是否同样能逆转TSC患者衍生神经元中发现的细胞和功能缺陷。我们的结果表明，新型选择性mTORC1抑制剂几乎完全逆转了iPSC衍生神经元的细胞和功能缺陷，其方式和程度与雷帕霉素相似，因为与用二甲基亚砜（DMSO）处理的细胞相比，它们都逆转并使神经元的过度兴奋和异常形态接近正常。这些数据表明，mTORC1特异性化合物可以提供与雷帕霉素相似的临床治疗益处，而没有相同的副作用。
