mTORC1-selective inhibitors rescue cellular phenotypes in TSC iPSC-derived neurons
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 no...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2025.1595880/full |
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| author | Elizabeth D. Buttermore Elizabeth D. Buttermore Gayathri Rajaram Srinivasan Gayathri Rajaram Srinivasan Hellen Jumo Hellen Jumo Amanda C. Swanson Amanda C. Swanson Benjamin O’Kelly Benjamin O’Kelly Nina R. Makhortova Nina R. Makhortova Nina R. Makhortova Mustafa Sahin Mustafa Sahin Mustafa Sahin Stelios T. Tzannis |
| author_facet | Elizabeth D. Buttermore Elizabeth D. Buttermore Gayathri Rajaram Srinivasan Gayathri Rajaram Srinivasan Hellen Jumo Hellen Jumo Amanda C. Swanson Amanda C. Swanson Benjamin O’Kelly Benjamin O’Kelly Nina R. Makhortova Nina R. Makhortova Nina R. Makhortova Mustafa Sahin Mustafa Sahin Mustafa Sahin Stelios T. Tzannis |
| author_sort | Elizabeth D. Buttermore |
| collection | DOAJ |
| description | 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 TSC1 or TSC2 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 TSC2–/– 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. |
| format | Article |
| id | doaj-art-33de48ecda0a4afdac33b237d17afb39 |
| institution | DOAJ |
| issn | 1662-453X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj-art-33de48ecda0a4afdac33b237d17afb392025-08-20T02:45:30ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2025-07-011910.3389/fnins.2025.15958801595880mTORC1-selective inhibitors rescue cellular phenotypes in TSC iPSC-derived neuronsElizabeth D. Buttermore0Elizabeth D. Buttermore1Gayathri Rajaram Srinivasan2Gayathri Rajaram Srinivasan3Hellen Jumo4Hellen Jumo5Amanda C. Swanson6Amanda C. Swanson7Benjamin O’Kelly8Benjamin O’Kelly9Nina R. Makhortova10Nina R. Makhortova11Nina R. Makhortova12Mustafa Sahin13Mustafa Sahin14Mustafa Sahin15Stelios T. Tzannis16Human Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA, United StatesF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, United StatesHuman Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA, United StatesF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, United StatesF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, United StatesDepartment of Neurology, Harvard Medical School, Boston, MA, United StatesHuman Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA, United StatesF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, United StatesHuman Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA, United StatesF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, United StatesHuman Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA, United StatesF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, United StatesDepartment of Neurology, Harvard Medical School, Boston, MA, United StatesHuman Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA, United StatesF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, United StatesDepartment of Neurology, Harvard Medical School, Boston, MA, United StatesAeovian Pharmaceuticals, Inc., Berkeley, CA, United StatesThe 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 TSC1 or TSC2 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 TSC2–/– 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.https://www.frontiersin.org/articles/10.3389/fnins.2025.1595880/fullmTORC1mTORC2iPSC-derived neuronsTSC2mTORhyperexcitability |
| spellingShingle | Elizabeth D. Buttermore Elizabeth D. Buttermore Gayathri Rajaram Srinivasan Gayathri Rajaram Srinivasan Hellen Jumo Hellen Jumo Amanda C. Swanson Amanda C. Swanson Benjamin O’Kelly Benjamin O’Kelly Nina R. Makhortova Nina R. Makhortova Nina R. Makhortova Mustafa Sahin Mustafa Sahin Mustafa Sahin Stelios T. Tzannis mTORC1-selective inhibitors rescue cellular phenotypes in TSC iPSC-derived neurons Frontiers in Neuroscience mTORC1 mTORC2 iPSC-derived neurons TSC2 mTOR hyperexcitability |
| title | mTORC1-selective inhibitors rescue cellular phenotypes in TSC iPSC-derived neurons |
| title_full | mTORC1-selective inhibitors rescue cellular phenotypes in TSC iPSC-derived neurons |
| title_fullStr | mTORC1-selective inhibitors rescue cellular phenotypes in TSC iPSC-derived neurons |
| title_full_unstemmed | mTORC1-selective inhibitors rescue cellular phenotypes in TSC iPSC-derived neurons |
| title_short | mTORC1-selective inhibitors rescue cellular phenotypes in TSC iPSC-derived neurons |
| title_sort | mtorc1 selective inhibitors rescue cellular phenotypes in tsc ipsc derived neurons |
| topic | mTORC1 mTORC2 iPSC-derived neurons TSC2 mTOR hyperexcitability |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2025.1595880/full |
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