A bitopic mTORC inhibitor reverses phenotypes in a tuberous sclerosis complex model
Abstract 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...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-08345-z |
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| author | Sulagna Mukherjee Matthew J. Wolan Mary K. Scott Victoria A. Riley Aidan M. Sokolov David M. Feliciano |
| author_facet | Sulagna Mukherjee Matthew J. Wolan Mary K. Scott Victoria A. Riley Aidan M. Sokolov David M. Feliciano |
| author_sort | Sulagna Mukherjee |
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| description | Abstract 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. |
| format | Article |
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| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-0da87cf73ff2455d9d8b100063f3a13a2025-08-20T03:37:27ZengNature PortfolioScientific Reports2045-23222025-07-0115111410.1038/s41598-025-08345-zA bitopic mTORC inhibitor reverses phenotypes in a tuberous sclerosis complex modelSulagna Mukherjee0Matthew J. Wolan1Mary K. Scott2Victoria A. Riley3Aidan M. Sokolov4David M. Feliciano5Department of Biological Sciences, Clemson UniversityDepartment of Biological Sciences, Clemson UniversityDepartment of Biological Sciences, Clemson UniversityDepartment of Biological Sciences, Clemson UniversityDepartment of Biological Sciences, Clemson UniversityDepartment of Biological Sciences, Clemson UniversityAbstract 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.https://doi.org/10.1038/s41598-025-08345-zTsc2Tuberous sclerosis complexTSCSEGASubependymal giant cell AstrocytomaSubependymal nodule |
| spellingShingle | Sulagna Mukherjee Matthew J. Wolan Mary K. Scott Victoria A. Riley Aidan M. Sokolov David M. Feliciano A bitopic mTORC inhibitor reverses phenotypes in a tuberous sclerosis complex model Scientific Reports Tsc2 Tuberous sclerosis complex TSC SEGA Subependymal giant cell Astrocytoma Subependymal nodule |
| title | A bitopic mTORC inhibitor reverses phenotypes in a tuberous sclerosis complex model |
| title_full | A bitopic mTORC inhibitor reverses phenotypes in a tuberous sclerosis complex model |
| title_fullStr | A bitopic mTORC inhibitor reverses phenotypes in a tuberous sclerosis complex model |
| title_full_unstemmed | A bitopic mTORC inhibitor reverses phenotypes in a tuberous sclerosis complex model |
| title_short | A bitopic mTORC inhibitor reverses phenotypes in a tuberous sclerosis complex model |
| title_sort | bitopic mtorc inhibitor reverses phenotypes in a tuberous sclerosis complex model |
| topic | Tsc2 Tuberous sclerosis complex TSC SEGA Subependymal giant cell Astrocytoma Subependymal nodule |
| url | https://doi.org/10.1038/s41598-025-08345-z |
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