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http://hdl.handle.net/2445/184430
Title: | Decreased glycogen synthase kinase-3 levels and activity contribute to Huntington's disease |
Author: | Fernández-Nogales, Marta Hernández, Félix Miguez, Andrés Alberch i Vié, Jordi, 1959- Ginés Padrós, Silvia Pérez Navarro, Esther Lucas, José J. |
Keywords: | Corea de Huntington Proteïnes quinases Inhibidors enzimàtics Malalties neurodegeneratives Cinètica enzimàtica Huntington's chorea Protein kinases Enzyme inhibitors Neurodegenerative Diseases Enzyme kinetics |
Issue Date: | 1-Sep-2015 |
Publisher: | Oxford University Press |
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. |
Note: | Versió postprint del document publicat a: https://doi.org/10.1093/hmg/ddv224 |
It is part of: | Human Molecular Genetics, 2015, vol. 24, num. 17, p. 5040-5052 |
URI: | http://hdl.handle.net/2445/184430 |
Related resource: | https://doi.org/10.1093/hmg/ddv224 |
ISSN: | 0964-6906 |
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 |
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654617.pdf | 1.63 MB | Adobe PDF | View/Open |
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