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Exposure to the Amino Acids Histidine, Lysine, and Threonine Reduces mTOR Activity and Affects Neurodevelopment in a Human Cerebral Organoid Model

Evidence of the impact of nutrition on human brain development is compelling. Previous in vitro and in vivo results show that three specific amino acids, histidine, lysine, and threonine, synergistically inhibit mTOR activity and behavior. Therefore, the prenatal availability of these amino acids co...

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Autores principales: Berdenis van Berlekom, Amber, Kübler, Raphael, Hoogeboom, Jeske W., Vonk, Daniëlle, Sluijs, Jacqueline A., Pasterkamp, R. Jeroen, Middeldorp, Jinte, Kraneveld, Aletta D., Garssen, Johan, Kahn, René S., Hol, Elly M., de Witte, Lot D., Boks, Marco P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9145399/
https://www.ncbi.nlm.nih.gov/pubmed/35631316
http://dx.doi.org/10.3390/nu14102175
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author Berdenis van Berlekom, Amber
Kübler, Raphael
Hoogeboom, Jeske W.
Vonk, Daniëlle
Sluijs, Jacqueline A.
Pasterkamp, R. Jeroen
Middeldorp, Jinte
Kraneveld, Aletta D.
Garssen, Johan
Kahn, René S.
Hol, Elly M.
de Witte, Lot D.
Boks, Marco P.
author_facet Berdenis van Berlekom, Amber
Kübler, Raphael
Hoogeboom, Jeske W.
Vonk, Daniëlle
Sluijs, Jacqueline A.
Pasterkamp, R. Jeroen
Middeldorp, Jinte
Kraneveld, Aletta D.
Garssen, Johan
Kahn, René S.
Hol, Elly M.
de Witte, Lot D.
Boks, Marco P.
author_sort Berdenis van Berlekom, Amber
collection PubMed
description Evidence of the impact of nutrition on human brain development is compelling. Previous in vitro and in vivo results show that three specific amino acids, histidine, lysine, and threonine, synergistically inhibit mTOR activity and behavior. Therefore, the prenatal availability of these amino acids could be important for human neurodevelopment. However, methods to study the underlying mechanisms in a human model of neurodevelopment are limited. Here, we pioneer the use of human cerebral organoids to investigate the impact of amino acid supplementation on neurodevelopment. In this study, cerebral organoids were exposed to 10 mM and 50 mM of the amino acids threonine, histidine, and lysine. The impact was determined by measuring mTOR activity using Western blots, general cerebral organoid size, and gene expression by RNA sequencing. Exposure to threonine, histidine, and lysine led to decreased mTOR activity and markedly reduced organoid size, supporting findings in rodent studies. RNA sequencing identified comprehensive changes in gene expression, with enrichment in genes related to specific biological processes (among which are mTOR signaling and immune function) and to specific cell types, including proliferative precursor cells, microglia, and astrocytes. Altogether, cerebral organoids are responsive to nutritional exposure by increasing specific amino acid concentrations and reflect findings from previous rodent studies. Threonine, histidine, and lysine exposure impacts the early development of human cerebral organoids, illustrated by the inhibition of mTOR activity, reduced size, and altered gene expression.
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spelling pubmed-91453992022-05-29 Exposure to the Amino Acids Histidine, Lysine, and Threonine Reduces mTOR Activity and Affects Neurodevelopment in a Human Cerebral Organoid Model Berdenis van Berlekom, Amber Kübler, Raphael Hoogeboom, Jeske W. Vonk, Daniëlle Sluijs, Jacqueline A. Pasterkamp, R. Jeroen Middeldorp, Jinte Kraneveld, Aletta D. Garssen, Johan Kahn, René S. Hol, Elly M. de Witte, Lot D. Boks, Marco P. Nutrients Article Evidence of the impact of nutrition on human brain development is compelling. Previous in vitro and in vivo results show that three specific amino acids, histidine, lysine, and threonine, synergistically inhibit mTOR activity and behavior. Therefore, the prenatal availability of these amino acids could be important for human neurodevelopment. However, methods to study the underlying mechanisms in a human model of neurodevelopment are limited. Here, we pioneer the use of human cerebral organoids to investigate the impact of amino acid supplementation on neurodevelopment. In this study, cerebral organoids were exposed to 10 mM and 50 mM of the amino acids threonine, histidine, and lysine. The impact was determined by measuring mTOR activity using Western blots, general cerebral organoid size, and gene expression by RNA sequencing. Exposure to threonine, histidine, and lysine led to decreased mTOR activity and markedly reduced organoid size, supporting findings in rodent studies. RNA sequencing identified comprehensive changes in gene expression, with enrichment in genes related to specific biological processes (among which are mTOR signaling and immune function) and to specific cell types, including proliferative precursor cells, microglia, and astrocytes. Altogether, cerebral organoids are responsive to nutritional exposure by increasing specific amino acid concentrations and reflect findings from previous rodent studies. Threonine, histidine, and lysine exposure impacts the early development of human cerebral organoids, illustrated by the inhibition of mTOR activity, reduced size, and altered gene expression. MDPI 2022-05-23 /pmc/articles/PMC9145399/ /pubmed/35631316 http://dx.doi.org/10.3390/nu14102175 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Berdenis van Berlekom, Amber
Kübler, Raphael
Hoogeboom, Jeske W.
Vonk, Daniëlle
Sluijs, Jacqueline A.
Pasterkamp, R. Jeroen
Middeldorp, Jinte
Kraneveld, Aletta D.
Garssen, Johan
Kahn, René S.
Hol, Elly M.
de Witte, Lot D.
Boks, Marco P.
Exposure to the Amino Acids Histidine, Lysine, and Threonine Reduces mTOR Activity and Affects Neurodevelopment in a Human Cerebral Organoid Model
title Exposure to the Amino Acids Histidine, Lysine, and Threonine Reduces mTOR Activity and Affects Neurodevelopment in a Human Cerebral Organoid Model
title_full Exposure to the Amino Acids Histidine, Lysine, and Threonine Reduces mTOR Activity and Affects Neurodevelopment in a Human Cerebral Organoid Model
title_fullStr Exposure to the Amino Acids Histidine, Lysine, and Threonine Reduces mTOR Activity and Affects Neurodevelopment in a Human Cerebral Organoid Model
title_full_unstemmed Exposure to the Amino Acids Histidine, Lysine, and Threonine Reduces mTOR Activity and Affects Neurodevelopment in a Human Cerebral Organoid Model
title_short Exposure to the Amino Acids Histidine, Lysine, and Threonine Reduces mTOR Activity and Affects Neurodevelopment in a Human Cerebral Organoid Model
title_sort exposure to the amino acids histidine, lysine, and threonine reduces mtor activity and affects neurodevelopment in a human cerebral organoid model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9145399/
https://www.ncbi.nlm.nih.gov/pubmed/35631316
http://dx.doi.org/10.3390/nu14102175
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