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2015-09-01

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/184430

Decreased glycogen synthase kinase-3 levels and activity contribute to Huntington's disease

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https://doi.org/10.1093/hmg/ddv224

Resum

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.

Matèries

Corea de Huntington, Proteïnes quinases, Inhibidors enzimàtics, Malalties neurodegeneratives, Cinètica enzimàtica

Matèries (anglès)

Huntington's chorea, Protein kinases, Enzyme inhibitors, Neurodegenerative Diseases, Enzyme kinetics

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Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Publicacions de projectes de recerca finançats per la UE

Citació

FERNÁNDEZ-NOGALES, Marta, et al. Decreased glycogen synthase kinase-3 levels and activity contribute to Huntington's disease. Human Molecular Genetics. 2015. Vol. 24, num. 17, pags. 5040-5052. ISSN 0964-6906. [consulted: 30 of June of 2026]. Available at: https://hdl.handle.net/2445/184430

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