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Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency

Creatine transporter deficiency (CTD), a leading cause of intellectual disability is a result of the mutation in the gene encoding the creatine transporter SLC6A8, which prevents creatine uptake into the brain, causing mental retardation, expressive speech and language delay, autistic-like behavior...

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Autores principales: Mabondzo, Aloïse, Harati, Rania, Broca-Brisson, Léa, Guyot, Anne-Cécile, Costa, Narciso, Cacciante, Francesco, Putignano, Elena, Baroncelli, Laura, Skelton, Matthew R., Saab, Cathy, Martini, Emmanuelle, Benech, Henri, Joudinaud, Thomas, Gaillard, Jean-Charles, Armengaud, Jean, Hamoudi, Rifat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103630/
https://www.ncbi.nlm.nih.gov/pubmed/37063368
http://dx.doi.org/10.3389/fnmol.2023.1118707
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author Mabondzo, Aloïse
Harati, Rania
Broca-Brisson, Léa
Guyot, Anne-Cécile
Costa, Narciso
Cacciante, Francesco
Putignano, Elena
Baroncelli, Laura
Skelton, Matthew R.
Saab, Cathy
Martini, Emmanuelle
Benech, Henri
Joudinaud, Thomas
Gaillard, Jean-Charles
Armengaud, Jean
Hamoudi, Rifat
author_facet Mabondzo, Aloïse
Harati, Rania
Broca-Brisson, Léa
Guyot, Anne-Cécile
Costa, Narciso
Cacciante, Francesco
Putignano, Elena
Baroncelli, Laura
Skelton, Matthew R.
Saab, Cathy
Martini, Emmanuelle
Benech, Henri
Joudinaud, Thomas
Gaillard, Jean-Charles
Armengaud, Jean
Hamoudi, Rifat
author_sort Mabondzo, Aloïse
collection PubMed
description Creatine transporter deficiency (CTD), a leading cause of intellectual disability is a result of the mutation in the gene encoding the creatine transporter SLC6A8, which prevents creatine uptake into the brain, causing mental retardation, expressive speech and language delay, autistic-like behavior and epilepsy. Preclinical in vitro and in vivo data indicate that dodecyl creatine ester (DCE) which increases the creatine brain content, might be a therapeutic option for CTD patients. To gain a better understanding of the pathophysiology and DCE treatment efficacy in CTD, this study focuses on the identification of biomarkers related to cognitive improvement in a Slc6a8 knockout mouse model (Slc6a8−/y) engineered to mimic the clinical features of CTD patients which have low brain creatine content. Shotgun proteomics analysis of 4,035 proteins in four different brain regions; the cerebellum, cortex, hippocampus (associated with cognitive functions) and brain stem, and muscle as a control, was performed in 24 mice. Comparison of the protein abundance in the four brain regions between DCE-treated intranasally Slc6a8−/y mice and wild type and DCE-treated Slc6a8−/y and vehicle group identified 14 biomarkers, shedding light on the mechanism of action of DCE. Integrative bioinformatics and statistical modeling identified key proteins in CTD, including KIF1A and PLCB1. The abundance of these proteins in the four brain regions was significantly correlated with both the object recognition and the Y-maze tests. Our findings suggest a major role for PLCB1, KIF1A, and associated molecules in the pathogenesis of CTD.
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spelling pubmed-101036302023-04-15 Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency Mabondzo, Aloïse Harati, Rania Broca-Brisson, Léa Guyot, Anne-Cécile Costa, Narciso Cacciante, Francesco Putignano, Elena Baroncelli, Laura Skelton, Matthew R. Saab, Cathy Martini, Emmanuelle Benech, Henri Joudinaud, Thomas Gaillard, Jean-Charles Armengaud, Jean Hamoudi, Rifat Front Mol Neurosci Molecular Neuroscience Creatine transporter deficiency (CTD), a leading cause of intellectual disability is a result of the mutation in the gene encoding the creatine transporter SLC6A8, which prevents creatine uptake into the brain, causing mental retardation, expressive speech and language delay, autistic-like behavior and epilepsy. Preclinical in vitro and in vivo data indicate that dodecyl creatine ester (DCE) which increases the creatine brain content, might be a therapeutic option for CTD patients. To gain a better understanding of the pathophysiology and DCE treatment efficacy in CTD, this study focuses on the identification of biomarkers related to cognitive improvement in a Slc6a8 knockout mouse model (Slc6a8−/y) engineered to mimic the clinical features of CTD patients which have low brain creatine content. Shotgun proteomics analysis of 4,035 proteins in four different brain regions; the cerebellum, cortex, hippocampus (associated with cognitive functions) and brain stem, and muscle as a control, was performed in 24 mice. Comparison of the protein abundance in the four brain regions between DCE-treated intranasally Slc6a8−/y mice and wild type and DCE-treated Slc6a8−/y and vehicle group identified 14 biomarkers, shedding light on the mechanism of action of DCE. Integrative bioinformatics and statistical modeling identified key proteins in CTD, including KIF1A and PLCB1. The abundance of these proteins in the four brain regions was significantly correlated with both the object recognition and the Y-maze tests. Our findings suggest a major role for PLCB1, KIF1A, and associated molecules in the pathogenesis of CTD. Frontiers Media S.A. 2023-03-24 /pmc/articles/PMC10103630/ /pubmed/37063368 http://dx.doi.org/10.3389/fnmol.2023.1118707 Text en Copyright © 2023 Mabondzo, Harati, Broca-Brisson, Guyot, Costa, Cacciante, Putignano, Baroncelli, Skelton, Saab, Martini, Benech, Joudinaud, Gaillard, Armengaud and Hamoudi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Neuroscience
Mabondzo, Aloïse
Harati, Rania
Broca-Brisson, Léa
Guyot, Anne-Cécile
Costa, Narciso
Cacciante, Francesco
Putignano, Elena
Baroncelli, Laura
Skelton, Matthew R.
Saab, Cathy
Martini, Emmanuelle
Benech, Henri
Joudinaud, Thomas
Gaillard, Jean-Charles
Armengaud, Jean
Hamoudi, Rifat
Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency
title Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency
title_full Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency
title_fullStr Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency
title_full_unstemmed Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency
title_short Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency
title_sort dodecyl creatine ester improves cognitive function and identifies key protein drivers including kif1a and plcb1 in a mouse model of creatine transporter deficiency
topic Molecular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103630/
https://www.ncbi.nlm.nih.gov/pubmed/37063368
http://dx.doi.org/10.3389/fnmol.2023.1118707
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