title: Decreased glycogen synthase kinase-3 levels and activity contribute to Huntington's disease.
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.
authors.affiliation: Center for Molecular Biology "Severo Ochoa" (CBMSO) CSIC/UAM, 28049 Madrid, Spain, Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Fernández-Nogales
authors.affiliation: Center for Molecular Biology "Severo Ochoa" (CBMSO) CSIC/UAM, 28049 Madrid, Spain, Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Félix
authors.initials: F
authors.lastname: Hernández
authors.affiliation: Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, Departament de Biologia, Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Miguez
authors.affiliation: Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, Departament de Biologia, Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.affiliation: Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, Departament de Biologia, Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ginés
authors.affiliation: Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, Departament de Biologia, Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Navarro
authors.affiliation: Center for Molecular Biology "Severo Ochoa" (CBMSO) CSIC/UAM, 28049 Madrid, Spain, Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, jjlucas@cbm.csic.es.
authors.forename: José J
authors.initials: JJ
authors.lastname: Lucas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001284:Atrophy; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D003071:Cognition; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009043:Motor Activity / Q000235:genetics; D010641:Phenotype
chemical_list: D038362:Glycogen Synthase Kinase 3