Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia

Hyperhomocysteinemia due to cystathionine beta synthase (CBS) deficiency is associated with diverse cognitive dysfunction. Considering the role of the serine/threonine kinase DYRK1A, not only in developmental defects with life-long structural and functional consequences, but also in multiple neurode...

Descripción completa

Detalles Bibliográficos
Autores: Baloula, Vanessa, Fructuoso, Marta, Kassis, Nadim, Gueddouri, Dalale, Paul, Jean-Louis, Janel, Nathalie
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/43100
Acceso en línea:http://hdl.handle.net/10230/43100
http://dx.doi.org/10.1016/j.redox.2018.08.015
Access Level:acceso abierto
Palabra clave:Hyperhomocysteinemia
DYRK1A
AAV
Brain
RTK pathway
NFkB pathway
id ES_a3063a502d10b4e3de4fa4acb13f8c73
oai_identifier_str oai:repositori.upf.edu:10230/43100
network_acronym_str ES
network_name_str España
repository_id_str
spelling Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemiaBaloula, VanessaFructuoso, MartaKassis, NadimGueddouri, DalalePaul, Jean-LouisJanel, NathalieHyperhomocysteinemiaDYRK1AAAVBrainRTK pathwayNFkB pathwayHyperhomocysteinemia due to cystathionine beta synthase (CBS) deficiency is associated with diverse cognitive dysfunction. Considering the role of the serine/threonine kinase DYRK1A, not only in developmental defects with life-long structural and functional consequences, but also in multiple neurodegenerative diseases, its protein expression and kinase activity has been analyzed in brain of heterozygous CBS deficient mice and found to be increased. We previously demonstrated that specific liver treatment with an adenovirus expressing Dyrk1A normalizes hepatic DYRK1A level and decreases hyperhomocysteinemia in mice with moderate to intermediate hyperhomocysteinemia. We here use a hepatocyte-specific recombinant adeno-associated viral (AAV) serotype 8-mediated DYRK1A gene therapy (AAV2/8-DYRK1A) to analyze the effect of hepatic Dyrk1A gene transfer on some altered molecular mechanisms in brain of mice with intermediate hyperhomocysteinemia. Our selective hepatic treatment alleviates altered DYRK1A protein level and signaling pathways in brain of mice, the MAPK/ERK and PI3K/Akt pathways initiated by receptor tyrosine kinase, the BDNF dependent TrkB pathway, and NFkB pathway. These results demonstrate the positive effect of AAV2/8-DYRK1A gene transfer on neuropathological and inflammatory processes in brain of mice with intermediate hyperhomocysteinemia.Elsevier201920192018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/43100http://dx.doi.org/10.1016/j.redox.2018.08.015reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésRedox Biol. 2018; 19:200-209© 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).http://creativecommons.org/licenses/BY/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/431002026-06-12T07:21:37Z
dc.title.none.fl_str_mv Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia
title Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia
spellingShingle Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia
Baloula, Vanessa
Hyperhomocysteinemia
DYRK1A
AAV
Brain
RTK pathway
NFkB pathway
title_short Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia
title_full Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia
title_fullStr Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia
title_full_unstemmed Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia
title_sort Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia
dc.creator.none.fl_str_mv Baloula, Vanessa
Fructuoso, Marta
Kassis, Nadim
Gueddouri, Dalale
Paul, Jean-Louis
Janel, Nathalie
author Baloula, Vanessa
author_facet Baloula, Vanessa
Fructuoso, Marta
Kassis, Nadim
Gueddouri, Dalale
Paul, Jean-Louis
Janel, Nathalie
author_role author
author2 Fructuoso, Marta
Kassis, Nadim
Gueddouri, Dalale
Paul, Jean-Louis
Janel, Nathalie
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Hyperhomocysteinemia
DYRK1A
AAV
Brain
RTK pathway
NFkB pathway
topic Hyperhomocysteinemia
DYRK1A
AAV
Brain
RTK pathway
NFkB pathway
description Hyperhomocysteinemia due to cystathionine beta synthase (CBS) deficiency is associated with diverse cognitive dysfunction. Considering the role of the serine/threonine kinase DYRK1A, not only in developmental defects with life-long structural and functional consequences, but also in multiple neurodegenerative diseases, its protein expression and kinase activity has been analyzed in brain of heterozygous CBS deficient mice and found to be increased. We previously demonstrated that specific liver treatment with an adenovirus expressing Dyrk1A normalizes hepatic DYRK1A level and decreases hyperhomocysteinemia in mice with moderate to intermediate hyperhomocysteinemia. We here use a hepatocyte-specific recombinant adeno-associated viral (AAV) serotype 8-mediated DYRK1A gene therapy (AAV2/8-DYRK1A) to analyze the effect of hepatic Dyrk1A gene transfer on some altered molecular mechanisms in brain of mice with intermediate hyperhomocysteinemia. Our selective hepatic treatment alleviates altered DYRK1A protein level and signaling pathways in brain of mice, the MAPK/ERK and PI3K/Akt pathways initiated by receptor tyrosine kinase, the BDNF dependent TrkB pathway, and NFkB pathway. These results demonstrate the positive effect of AAV2/8-DYRK1A gene transfer on neuropathological and inflammatory processes in brain of mice with intermediate hyperhomocysteinemia.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
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/10230/43100
http://dx.doi.org/10.1016/j.redox.2018.08.015
url http://hdl.handle.net/10230/43100
http://dx.doi.org/10.1016/j.redox.2018.08.015
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Redox Biol. 2018; 19:200-209
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 Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869415346198282240
score 15.812429

Similares en LA Referencia