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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
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.
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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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