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Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network

Absence of the Fragile X Messenger Ribonucleoprotein 1 (FMRP) causes autism spectrum disorders and intellectual disability, commonly referred to as the Fragile X syndrome. FMRP is a negative regulator of protein translation and is essential for neuronal development and synapse formation. FMRP is a t...

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Autores principales: D’Incal, Claudio, Broos, Jitse, Torfs, Thierry, Kooy, R. Frank, Vanden Berghe, Wim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029738/
https://www.ncbi.nlm.nih.gov/pubmed/35456004
http://dx.doi.org/10.3390/cells11081325
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author D’Incal, Claudio
Broos, Jitse
Torfs, Thierry
Kooy, R. Frank
Vanden Berghe, Wim
author_facet D’Incal, Claudio
Broos, Jitse
Torfs, Thierry
Kooy, R. Frank
Vanden Berghe, Wim
author_sort D’Incal, Claudio
collection PubMed
description Absence of the Fragile X Messenger Ribonucleoprotein 1 (FMRP) causes autism spectrum disorders and intellectual disability, commonly referred to as the Fragile X syndrome. FMRP is a negative regulator of protein translation and is essential for neuronal development and synapse formation. FMRP is a target for several post-translational modifications (PTMs) such as phosphorylation and methylation, which tightly regulate its cellular functions. Studies have indicated the involvement of FMRP in a multitude of cellular pathways, and an absence of FMRP was shown to affect several neurotransmitter receptors, for example, the GABA receptor and intracellular signaling molecules such as Akt, ERK, mTOR, and GSK3. Interestingly, many of these molecules function as protein kinases or phosphatases and thus are potentially amendable by pharmacological treatment. Several treatments acting on these kinase-phosphatase systems have been shown to be successful in preclinical models; however, they have failed to convincingly show any improvements in clinical trials. In this review, we highlight the different protein kinase and phosphatase studies that have been performed in the Fragile X syndrome. In our opinion, some of the paradoxical study conclusions are potentially due to the lack of insight into integrative kinase signaling networks in the disease. Quantitative proteome analyses have been performed in several models for the FXS to determine global molecular processes in FXS. However, only one phosphoproteomics study has been carried out in Fmr1 knock-out mouse embryonic fibroblasts, and it showed dysfunctional protein kinase and phosphatase signaling hubs in the brain. This suggests that the further use of phosphoproteomics approaches in Fragile X syndrome holds promise for identifying novel targets for kinase inhibitor therapies.
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spelling pubmed-90297382022-04-23 Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network D’Incal, Claudio Broos, Jitse Torfs, Thierry Kooy, R. Frank Vanden Berghe, Wim Cells Review Absence of the Fragile X Messenger Ribonucleoprotein 1 (FMRP) causes autism spectrum disorders and intellectual disability, commonly referred to as the Fragile X syndrome. FMRP is a negative regulator of protein translation and is essential for neuronal development and synapse formation. FMRP is a target for several post-translational modifications (PTMs) such as phosphorylation and methylation, which tightly regulate its cellular functions. Studies have indicated the involvement of FMRP in a multitude of cellular pathways, and an absence of FMRP was shown to affect several neurotransmitter receptors, for example, the GABA receptor and intracellular signaling molecules such as Akt, ERK, mTOR, and GSK3. Interestingly, many of these molecules function as protein kinases or phosphatases and thus are potentially amendable by pharmacological treatment. Several treatments acting on these kinase-phosphatase systems have been shown to be successful in preclinical models; however, they have failed to convincingly show any improvements in clinical trials. In this review, we highlight the different protein kinase and phosphatase studies that have been performed in the Fragile X syndrome. In our opinion, some of the paradoxical study conclusions are potentially due to the lack of insight into integrative kinase signaling networks in the disease. Quantitative proteome analyses have been performed in several models for the FXS to determine global molecular processes in FXS. However, only one phosphoproteomics study has been carried out in Fmr1 knock-out mouse embryonic fibroblasts, and it showed dysfunctional protein kinase and phosphatase signaling hubs in the brain. This suggests that the further use of phosphoproteomics approaches in Fragile X syndrome holds promise for identifying novel targets for kinase inhibitor therapies. MDPI 2022-04-13 /pmc/articles/PMC9029738/ /pubmed/35456004 http://dx.doi.org/10.3390/cells11081325 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 Review
D’Incal, Claudio
Broos, Jitse
Torfs, Thierry
Kooy, R. Frank
Vanden Berghe, Wim
Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network
title Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network
title_full Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network
title_fullStr Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network
title_full_unstemmed Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network
title_short Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network
title_sort towards kinase inhibitor therapies for fragile x syndrome: tweaking twists in the autism spectrum kinase signaling network
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029738/
https://www.ncbi.nlm.nih.gov/pubmed/35456004
http://dx.doi.org/10.3390/cells11081325
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