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Decreased glycogen synthase kinase-3 levels and activity contribute to Huntington's disease
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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.
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FERNÁNDEZ-NOGALES, Marta, HERNÁNDEZ, Félix, MIGUEZ, Andrés, ALBERCH I VIÉ, Jordi, GINÉS PADRÓS, Silvia, PÉREZ NAVARRO, Esther, LUCAS, José j.. Decreased glycogen synthase kinase-3 levels and activity contribute to Huntington's disease. _Human Molecular Genetics_. 2015. Vol. 24, núm. 17, pàgs. 5040-5052. [consulta: 15 de gener de 2026]. ISSN: 0964-6906. [Disponible a: https://hdl.handle.net/2445/184430]