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http://hdl.handle.net/2445/184430
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DC Field | Value | Language |
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dc.contributor.author | Fernández-Nogales, Marta | - |
dc.contributor.author | Hernández, Félix | - |
dc.contributor.author | Miguez, Andrés | - |
dc.contributor.author | Alberch i Vié, Jordi, 1959- | - |
dc.contributor.author | Ginés Padrós, Silvia | - |
dc.contributor.author | Pérez Navarro, Esther | - |
dc.contributor.author | Lucas, José J. | - |
dc.date.accessioned | 2022-03-28T12:38:47Z | - |
dc.date.available | 2022-03-28T12:38:47Z | - |
dc.date.issued | 2015-09-01 | - |
dc.identifier.issn | 0964-6906 | - |
dc.identifier.uri | http://hdl.handle.net/2445/184430 | - |
dc.description.abstract | Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by brain atrophy particularly in striatum leading to personality changes, chorea and dementia. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase in the crossroad of many signaling pathways that is highly pleiotropic as it phosphorylates more than hundred substrates including structural, metabolic, and signaling proteins. Increased GSK-3 activity is believed to contribute to the pathogenesis of neurodegenerative diseases like Alzheimer's disease and GSK-3 inhibitors have been postulated as therapeutic agents for neurodegeneration. Regarding HD, GSK-3 inhibitors have shown beneficial effects in cell and invertebrate animal models but no evident efficacy in mouse models. Intriguingly, those studies were performed without interrogating GSK-3 level and activity in HD brain. Here we aim to explore the level and also the enzymatic activity of GSK-3 in the striatum and other less affected brain regions of HD patients and of the R6/1 mouse model to then elucidate the possible contribution of its alteration to HD pathogenesis by genetic manipulation in mice. We report a dramatic decrease in GSK-3 levels and activity in striatum and cortex of HD patients with similar results in the mouse model. Correction of the GSK-3 deficit in HD mice, by combining with transgenic mice with conditional GSK-3 expression, resulted in amelioration of their brain atrophy and behavioral motor and learning deficits. Thus, our results demonstrate that decreased brain GSK-3 contributes to HD neurological phenotype and open new therapeutic opportunities based on increasing GSK-3 activity or attenuating the harmful consequences of its decrease. | - |
dc.format.extent | 16 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Oxford University Press | - |
dc.relation.isformatof | Versió postprint del document publicat a: https://doi.org/10.1093/hmg/ddv224 | - |
dc.relation.ispartof | Human Molecular Genetics, 2015, vol. 24, num. 17, p. 5040-5052 | - |
dc.relation.uri | https://doi.org/10.1093/hmg/ddv224 | - |
dc.rights | (c) Fernández-Nogales, Marta et al., 2015 | - |
dc.source | Articles publicats en revistes (Biomedicina) | - |
dc.subject.classification | Corea de Huntington | - |
dc.subject.classification | Proteïnes quinases | - |
dc.subject.classification | Inhibidors enzimàtics | - |
dc.subject.classification | Malalties neurodegeneratives | - |
dc.subject.classification | Cinètica enzimàtica | - |
dc.subject.other | Huntington's chorea | - |
dc.subject.other | Protein kinases | - |
dc.subject.other | Enzyme inhibitors | - |
dc.subject.other | Neurodegenerative Diseases | - |
dc.subject.other | Enzyme kinetics | - |
dc.title | Decreased glycogen synthase kinase-3 levels and activity contribute to Huntington's disease | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/acceptedVersion | - |
dc.identifier.idgrec | 654617 | - |
dc.date.updated | 2022-03-28T12:38:47Z | - |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/FP7/229673/EU//BIOTRACK | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) Articles publicats en revistes (Biomedicina) Publicacions de projectes de recerca finançats per la UE |
Files in This Item:
File | Description | Size | Format | |
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654617.pdf | 1.63 MB | Adobe PDF | View/Open |
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