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Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment
FXS is the most common genetic cause of intellectual (ID) and autism spectrum disorders (ASD). FXS is caused by loss of FMRP, an RNA-binding protein involved in the translational regulation of a large number of neuronal mRNAs. Absence of FMRP has been shown to lead to elevated protein synthesis and...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251671/ https://www.ncbi.nlm.nih.gov/pubmed/32460900 http://dx.doi.org/10.1186/s13229-020-00350-5 |
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author | Utami, Kagistia Hana Yusof, Nur Amirah Binte Mohammad Kwa, Jing Eugene Peteri, Ulla-Kaisa Castrén, Maija L. Pouladi, Mahmoud A. |
author_facet | Utami, Kagistia Hana Yusof, Nur Amirah Binte Mohammad Kwa, Jing Eugene Peteri, Ulla-Kaisa Castrén, Maija L. Pouladi, Mahmoud A. |
author_sort | Utami, Kagistia Hana |
collection | PubMed |
description | FXS is the most common genetic cause of intellectual (ID) and autism spectrum disorders (ASD). FXS is caused by loss of FMRP, an RNA-binding protein involved in the translational regulation of a large number of neuronal mRNAs. Absence of FMRP has been shown to lead to elevated protein synthesis and is thought to be a major cause of the synaptic plasticity and behavioural deficits in FXS. The increase in protein synthesis results in part from abnormal activation of key protein translation pathways downstream of ERK1/2 and mTOR signalling. Pharmacological and genetic interventions that attenuate hyperactivation of these pathways can normalize levels of protein synthesis and improve phenotypic outcomes in animal models of FXS. Several efforts are currently underway to trial this strategy in patients with FXS. To date, elevated global protein synthesis as a result of FMRP loss has not been validated in the context of human neurons. Here, using an isogenic human stem cell-based model, we show that de novo protein synthesis is elevated in FMRP-deficient neural cells. We further show that this increase is associated with elevated ERK1/2 and Akt signalling and can be rescued by metformin treatment. Finally, we examined the effect of normalizing protein synthesis on phenotypic abnormalities in FMRP-deficient neural cells. We find that treatment with metformin attenuates the increase in proliferation of FMRP-deficient neural progenitor cells but not the neuronal deficits in neurite outgrowth. The elevated level of protein synthesis and the normalization of neural progenitor proliferation by metformin treatment were validated in additional control and FXS patient-derived hiPSC lines. Overall, our results validate that loss of FMRP results in elevated de novo protein synthesis in human neurons and suggest that approaches targeting this abnormality are likely to be of partial therapeutic benefit in FXS. |
format | Online Article Text |
id | pubmed-7251671 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-72516712020-06-04 Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment Utami, Kagistia Hana Yusof, Nur Amirah Binte Mohammad Kwa, Jing Eugene Peteri, Ulla-Kaisa Castrén, Maija L. Pouladi, Mahmoud A. Mol Autism Research FXS is the most common genetic cause of intellectual (ID) and autism spectrum disorders (ASD). FXS is caused by loss of FMRP, an RNA-binding protein involved in the translational regulation of a large number of neuronal mRNAs. Absence of FMRP has been shown to lead to elevated protein synthesis and is thought to be a major cause of the synaptic plasticity and behavioural deficits in FXS. The increase in protein synthesis results in part from abnormal activation of key protein translation pathways downstream of ERK1/2 and mTOR signalling. Pharmacological and genetic interventions that attenuate hyperactivation of these pathways can normalize levels of protein synthesis and improve phenotypic outcomes in animal models of FXS. Several efforts are currently underway to trial this strategy in patients with FXS. To date, elevated global protein synthesis as a result of FMRP loss has not been validated in the context of human neurons. Here, using an isogenic human stem cell-based model, we show that de novo protein synthesis is elevated in FMRP-deficient neural cells. We further show that this increase is associated with elevated ERK1/2 and Akt signalling and can be rescued by metformin treatment. Finally, we examined the effect of normalizing protein synthesis on phenotypic abnormalities in FMRP-deficient neural cells. We find that treatment with metformin attenuates the increase in proliferation of FMRP-deficient neural progenitor cells but not the neuronal deficits in neurite outgrowth. The elevated level of protein synthesis and the normalization of neural progenitor proliferation by metformin treatment were validated in additional control and FXS patient-derived hiPSC lines. Overall, our results validate that loss of FMRP results in elevated de novo protein synthesis in human neurons and suggest that approaches targeting this abnormality are likely to be of partial therapeutic benefit in FXS. BioMed Central 2020-05-27 /pmc/articles/PMC7251671/ /pubmed/32460900 http://dx.doi.org/10.1186/s13229-020-00350-5 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Utami, Kagistia Hana Yusof, Nur Amirah Binte Mohammad Kwa, Jing Eugene Peteri, Ulla-Kaisa Castrén, Maija L. Pouladi, Mahmoud A. Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment |
title | Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment |
title_full | Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment |
title_fullStr | Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment |
title_full_unstemmed | Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment |
title_short | Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment |
title_sort | elevated de novo protein synthesis in fmrp-deficient human neurons and its correction by metformin treatment |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251671/ https://www.ncbi.nlm.nih.gov/pubmed/32460900 http://dx.doi.org/10.1186/s13229-020-00350-5 |
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