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DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting
Caloric restriction and acute fasting are known to reduce seizures but through unclear mechanisms. mTOR signaling has been suggested as a potential mechanism for seizure protection from fasting. We demonstrate that brain mTORC1 signaling is reduced after acute fasting of mice and that neuronal mTORC...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508617/ https://www.ncbi.nlm.nih.gov/pubmed/36044864 http://dx.doi.org/10.1016/j.celrep.2022.111278 |
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author | Yuskaitis, Christopher J. Modasia, Jinita B. Schrötter, Sandra Rossitto, Leigh-Ana Groff, Karenna J. Morici, Christopher Mithal, Divakar S. Chakrabarty, Ram P. Chandel, Navdeep S. Manning, Brendan D. Sahin, Mustafa |
author_facet | Yuskaitis, Christopher J. Modasia, Jinita B. Schrötter, Sandra Rossitto, Leigh-Ana Groff, Karenna J. Morici, Christopher Mithal, Divakar S. Chakrabarty, Ram P. Chandel, Navdeep S. Manning, Brendan D. Sahin, Mustafa |
author_sort | Yuskaitis, Christopher J. |
collection | PubMed |
description | Caloric restriction and acute fasting are known to reduce seizures but through unclear mechanisms. mTOR signaling has been suggested as a potential mechanism for seizure protection from fasting. We demonstrate that brain mTORC1 signaling is reduced after acute fasting of mice and that neuronal mTORC1 integrates GATOR1 complex-mediated amino acid and tuberous sclerosis complex (TSC)-mediated growth factor signaling. Neuronal mTORC1 is most sensitive to withdrawal of leucine, arginine, and glutamine, which are dependent on DEPDC5, a component of the GATOR1 complex. Metabolomic analysis reveals that Depdc5 neuronal-specific knockout mice are resistant to sensing significant fluctuations in brain amino acid levels after fasting. Depdc5 neuronal-specific knockout mice are resistant to the protective effects of fasting on seizures or seizure-induced death. These results establish that acute fasting reduces seizure susceptibility in a DEPDC5-dependent manner. Modulation of nutrients upstream of GATOR1 and mTORC1 could offer a rational therapeutic strategy for epilepsy treatment. |
format | Online Article Text |
id | pubmed-9508617 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-95086172022-09-24 DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting Yuskaitis, Christopher J. Modasia, Jinita B. Schrötter, Sandra Rossitto, Leigh-Ana Groff, Karenna J. Morici, Christopher Mithal, Divakar S. Chakrabarty, Ram P. Chandel, Navdeep S. Manning, Brendan D. Sahin, Mustafa Cell Rep Article Caloric restriction and acute fasting are known to reduce seizures but through unclear mechanisms. mTOR signaling has been suggested as a potential mechanism for seizure protection from fasting. We demonstrate that brain mTORC1 signaling is reduced after acute fasting of mice and that neuronal mTORC1 integrates GATOR1 complex-mediated amino acid and tuberous sclerosis complex (TSC)-mediated growth factor signaling. Neuronal mTORC1 is most sensitive to withdrawal of leucine, arginine, and glutamine, which are dependent on DEPDC5, a component of the GATOR1 complex. Metabolomic analysis reveals that Depdc5 neuronal-specific knockout mice are resistant to sensing significant fluctuations in brain amino acid levels after fasting. Depdc5 neuronal-specific knockout mice are resistant to the protective effects of fasting on seizures or seizure-induced death. These results establish that acute fasting reduces seizure susceptibility in a DEPDC5-dependent manner. Modulation of nutrients upstream of GATOR1 and mTORC1 could offer a rational therapeutic strategy for epilepsy treatment. 2022-08-30 /pmc/articles/PMC9508617/ /pubmed/36044864 http://dx.doi.org/10.1016/j.celrep.2022.111278 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Yuskaitis, Christopher J. Modasia, Jinita B. Schrötter, Sandra Rossitto, Leigh-Ana Groff, Karenna J. Morici, Christopher Mithal, Divakar S. Chakrabarty, Ram P. Chandel, Navdeep S. Manning, Brendan D. Sahin, Mustafa DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting |
title | DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting |
title_full | DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting |
title_fullStr | DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting |
title_full_unstemmed | DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting |
title_short | DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting |
title_sort | depdc5-dependent mtorc1 signaling mechanisms are critical for the anti-seizure effects of acute fasting |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508617/ https://www.ncbi.nlm.nih.gov/pubmed/36044864 http://dx.doi.org/10.1016/j.celrep.2022.111278 |
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