Mukherjee Sulagna, Wolan Matthew J, Scott Mary K, Riley Victoria A, Sokolov Aidan M, Feliciano David M
Department of Biological Sciences, Clemson University, Clemson, SC, 29634-0314, USA.
Center for Human Genetics, Clemson University, Greenwood, SC, United States of America.
Sci Rep. 2025 Jul 1;15(1):20367. doi: 10.1038/s41598-025-08345-z.
Neural stem cells (NSCs) of the ventricular-subventricular zone (V-SVZ) generate diverse cell types including striatal glia during the neonatal period. NSC progeny uncouple stem cell-related mRNA transcripts from being translated during differentiation. We previously demonstrated that Tsc2 inactivation, which occurs in the neurodevelopmental disorder Tuberous Sclerosis Complex (TSC), prevents this from happening. Loss of Tsc2 causes hyperactivation of the protein kinase mechanistic target of rapamycin complex 1 (mTORC1), altered translation, retention of stemness in striatal glia, and the production of misplaced cytomegalic neurons having hypertrophic dendrite arbors. These phenotypes model characteristics of TSC hamartomas called subependymal giant cell astrocytomas (SEGAs). mTORC1 inhibitors called rapamycin analogs (rapalogs) are currently used to treat TSC and to assess the role of mTORC1 in regulating TSC-related phenotypes. Rapalogs are useful for treating SEGAs. However, they require lifelong application, have untoward side effects, and resistance may occur. They also incompletely inhibit mTORC1 and have limited efficacy. Rapalink-1 is a bitopic inhibitor that links rapamycin to a second-generation mTOR ATP competitive inhibitor, MLN0128. Here we explored the effect of Rapalink-1 on a TSC hamartoma model. The model is created by neonatal electroporation of mice having conditional Tsc2 genes. Prolonged Rapalink-1 treatment could be achieved with 1.5 or 3.0 mg/Kg injected intraperitoneally every five days. Rapalink-1 inhibited the mTORC1 pathway, decreased cell size, reduced neuron dendrite arbors, and reduced hamartoma size. In conclusion, these results demonstrate that cellular phenotypes in a TSC SEGA model are reversed by Rapalink-1 which may be useful to resolve TSC brain hamartomas.
脑室下区（V-SVZ）的神经干细胞（NSCs）在新生期可产生多种细胞类型，包括纹状体神经胶质细胞。神经干细胞后代在分化过程中会使与干细胞相关的mRNA转录本停止翻译。我们之前证明，在神经发育障碍结节性硬化症（TSC）中发生的Tsc2失活会阻止这种情况发生。Tsc2的缺失会导致蛋白激酶雷帕霉素复合物1（mTORC1）过度激活、翻译改变、纹状体神经胶质细胞中干性的保留，以及产生具有肥大树突分支的异位巨细胞神经元。这些表型模拟了TSC错构瘤（称为室管膜下巨细胞星形细胞瘤，SEGAs）的特征。目前，称为雷帕霉素类似物（rapalogs）的mTORC1抑制剂用于治疗TSC，并评估mTORC1在调节TSC相关表型中的作用。Rapalogs对治疗SEGAs很有用。然而，它们需要终身使用，有不良副作用，且可能会产生耐药性。它们还不能完全抑制mTORC1，疗效有限。Rapalink-1是一种双位点抑制剂，它将雷帕霉素与第二代mTOR ATP竞争性抑制剂MLN0128连接起来。在这里，我们探讨了Rapalink-1对TSC错构瘤模型的影响。该模型是通过对具有条件性Tsc2基因的小鼠进行新生期电穿孔创建的。每五天腹腔注射1.5或3.0 mg/Kg的Rapalink-1可实现长期治疗。Rapalink-1抑制了mTORC1通路，减小了细胞大小，减少了神经元树突分支，并减小了错构瘤大小。总之，这些结果表明，Rapalink-1可逆转TSC SEGA模型中的细胞表型，这可能有助于解决TSC脑错构瘤问题。
