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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.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.issn 2213-2317
dc.identifier.uri http://hdl.handle.net/10230/43100
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.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.uri http://creativecommons.org/licenses/BY/4.0/
dc.title Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1016/j.redox.2018.08.015
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.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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