Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia
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- dc.contributor.author Baloula, Vanessa
- dc.contributor.author Fructuoso, Marta
- dc.contributor.author Kassis, Nadim
- dc.contributor.author Gueddouri, Dalale
- dc.contributor.author Paul, Jean-Louis
- dc.contributor.author Janel, Nathalie
- dc.date.accessioned 2019-12-05T08:37:59Z
- dc.date.available 2019-12-05T08:37:59Z
- dc.date.issued 2018
- dc.description.abstract 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.
- dc.format.mimetype application/pdf
- dc.identifier.citation Baloula V, Fructuoso M, Kassis N, Gueddouri D, Paul JL, Janel N. Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia. Redox Biol. 2018; 19:200-209. DOI 10.1016/j.redox.2018.08.015
- dc.identifier.doi http://dx.doi.org/10.1016/j.redox.2018.08.015
- dc.identifier.issn 2213-2317
- dc.identifier.uri http://hdl.handle.net/10230/43100
- dc.language.iso eng
- dc.publisher Elsevier
- dc.relation.ispartof Redox Biol. 2018; 19:200-209
- dc.rights © 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/).
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/BY/4.0/
- dc.subject.keyword Hyperhomocysteinemia
- dc.subject.keyword DYRK1A
- dc.subject.keyword AAV
- dc.subject.keyword Brain
- dc.subject.keyword RTK pathway
- dc.subject.keyword NFkB pathway
- dc.title Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion