Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene

Introduction: DYRK1A is a dual-specificity kinase that is overexpressed in Down syndrome (DS) and plays a key role in neurogenesis, neuronal differentiation and function, cognitive phenotypes, and aging. Dyrk1A has also been implicated in cerebellar abnormalities observed in association with DS, and...

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Authors: Ortega, Mireia, De Toma, Ilario, Fernández-Blanco, Álvaro, Calderón Moruno, Anna, Barahona, Lucía, Trullàs, Ramón, Sabidó Aguadé, Eduard, 1981-, Dierssen, Mara
Format: article
Status:Published version
Publication Date:2022
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/56066
Online Access:http://hdl.handle.net/10230/56066
http://dx.doi.org/10.3389/fnmol.2022.1015220
Access Level:Open access
Keyword:DYRK1A
Down syndrome
Cerebellum
Mitochondria
Oxidative phosphorylation system
Proteomics
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spelling Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate geneOrtega, MireiaDe Toma, IlarioFernández-Blanco, ÁlvaroCalderón Moruno, AnnaBarahona, LucíaTrullàs, RamónSabidó Aguadé, Eduard, 1981-Dierssen, MaraDYRK1ADown syndromeCerebellumMitochondriaOxidative phosphorylation systemProteomicsIntroduction: DYRK1A is a dual-specificity kinase that is overexpressed in Down syndrome (DS) and plays a key role in neurogenesis, neuronal differentiation and function, cognitive phenotypes, and aging. Dyrk1A has also been implicated in cerebellar abnormalities observed in association with DS, and normalization of Dyrk1A dosage rescues granular and Purkinje cell densities in a trisomic DS mouse model. However, the underlying molecular mechanisms governing these processes are unknown. Methods: To shed light on the effects of Dyrk1A overexpression in the cerebellum, here we investigated the cerebellar proteome in transgenic Dyrk1A overexpressing mice in basal conditions and after treatment with green tea extract containing epigallocatechin-3-gallate (EGCG), a DYRK1A inhibitor. Results and discussion: Our results showed that Dyrk1A overexpression alters oxidative phosphorylation and mitochondrial function in the cerebellum of transgenic mice. These alterations are significantly rescued upon EGCG-containing green tea extract treatment, suggesting that its effects in DS could depend in part on targeting mitochondria, as shown by the partially restoration by the treatment of the increased mtDNA copy number in TG non-treated mice.This research was funded by the Agencia Estatal de Investigación (PID2019-110755RB-I00/AEI/10.13039/501100011033), the European Union’s Horizon 2020 Framework Programme under grant agreement no 848077. This reflects only the author’s view and the European Commission is not responsible for any use that may be made of the information it contains. Jerôme Lejeune Foundation (grant number 2002), NIH Blueprint for Neuroscience Research (grant number: 1R01EB 028159-01), Marató TV3 (#2016/20-30), and EU Joint Programme—Neurodegenerative Disease Research (Heroes AC170006). The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech), and it is supported by “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2017SGR595). The CRG acknowledges the support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. The CIBER of Rare Diseases (CIBERER) is an initiative of the ISCIII.Frontiers202320232022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/56066http://dx.doi.org/10.3389/fnmol.2022.1015220reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésFront Mol Neurosci. 2022 Dec 15;15:1015220info:eu-repo/grantAgreement/EC/H2020/848077info:eu-repo/grantAgreement/ES/2PE/PID2019-110755RB-I00© 2022 Ortega, De Toma, Fernández-Blanco, Calderón, Barahona, Trullàs, Sabidó and Dierssen. 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.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/560662026-05-29T05:05:01Z
dc.title.none.fl_str_mv Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene
title Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene
spellingShingle Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene
Ortega, Mireia
DYRK1A
Down syndrome
Cerebellum
Mitochondria
Oxidative phosphorylation system
Proteomics
title_short Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene
title_full Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene
title_fullStr Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene
title_full_unstemmed Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene
title_sort Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene
dc.creator.none.fl_str_mv Ortega, Mireia
De Toma, Ilario
Fernández-Blanco, Álvaro
Calderón Moruno, Anna
Barahona, Lucía
Trullàs, Ramón
Sabidó Aguadé, Eduard, 1981-
Dierssen, Mara
author Ortega, Mireia
author_facet Ortega, Mireia
De Toma, Ilario
Fernández-Blanco, Álvaro
Calderón Moruno, Anna
Barahona, Lucía
Trullàs, Ramón
Sabidó Aguadé, Eduard, 1981-
Dierssen, Mara
author_role author
author2 De Toma, Ilario
Fernández-Blanco, Álvaro
Calderón Moruno, Anna
Barahona, Lucía
Trullàs, Ramón
Sabidó Aguadé, Eduard, 1981-
Dierssen, Mara
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv DYRK1A
Down syndrome
Cerebellum
Mitochondria
Oxidative phosphorylation system
Proteomics
topic DYRK1A
Down syndrome
Cerebellum
Mitochondria
Oxidative phosphorylation system
Proteomics
description Introduction: DYRK1A is a dual-specificity kinase that is overexpressed in Down syndrome (DS) and plays a key role in neurogenesis, neuronal differentiation and function, cognitive phenotypes, and aging. Dyrk1A has also been implicated in cerebellar abnormalities observed in association with DS, and normalization of Dyrk1A dosage rescues granular and Purkinje cell densities in a trisomic DS mouse model. However, the underlying molecular mechanisms governing these processes are unknown. Methods: To shed light on the effects of Dyrk1A overexpression in the cerebellum, here we investigated the cerebellar proteome in transgenic Dyrk1A overexpressing mice in basal conditions and after treatment with green tea extract containing epigallocatechin-3-gallate (EGCG), a DYRK1A inhibitor. Results and discussion: Our results showed that Dyrk1A overexpression alters oxidative phosphorylation and mitochondrial function in the cerebellum of transgenic mice. These alterations are significantly rescued upon EGCG-containing green tea extract treatment, suggesting that its effects in DS could depend in part on targeting mitochondria, as shown by the partially restoration by the treatment of the increased mtDNA copy number in TG non-treated mice.
publishDate 2022
dc.date.none.fl_str_mv 2022
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/56066
http://dx.doi.org/10.3389/fnmol.2022.1015220
url http://hdl.handle.net/10230/56066
http://dx.doi.org/10.3389/fnmol.2022.1015220
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Front Mol Neurosci. 2022 Dec 15;15:1015220
info:eu-repo/grantAgreement/EC/H2020/848077
info:eu-repo/grantAgreement/ES/2PE/PID2019-110755RB-I00
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers
publisher.none.fl_str_mv Frontiers
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
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repository.mail.fl_str_mv
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