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http://hdl.handle.net/2445/184510
Title: | Increased translation as a novel pathogenic mechanism in Huntington's disease |
Author: | Creus Muncunill, Jordi Badillos Rodríguez, Raquel Garcia-Forn, Marta Masana Nadal, Mercè García-Díaz Barriga, Gerardo Guisado Corcoll, Anna Alberch i Vié, Jordi, 1959- Malagelada Grau, Cristina Delgado García, José M. Gruart i Massó, Agnès Pérez Navarro, Esther |
Keywords: | Corea de Huntington Proteïnes Depressió psíquica Síntesi proteica Huntington's chorea Proteins Mental depression Protein synthesis |
Issue Date: | 1-Oct-2019 |
Publisher: | Oxford University Press |
Abstract: | Huntington's disease is a neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the huntingtin gene. Striatal projection neurons are mainly affected, leading to motor symptoms, but molecular mechanisms involved in their vulnerability are not fully characterized. Here, we show that eIF4E binding protein (4E-BP), a protein that inhibits translation, is inactivated in Huntington's disease striatum by increased phosphorylation. Accordingly, we detected aberrant de novo protein synthesis. Proteomic characterization indicates that translation specifically affects sets of proteins as we observed upregulation of ribosomal and oxidative phosphorylation proteins and downregulation of proteins related to neuronal structure and function. Interestingly, treatment with the translation inhibitor 4EGI-1 prevented R6/1 mice motor deficits, although corticostriatal long-term depression was not markedly changed in behaving animals. At the molecular level, injection of 4EGI-1 normalized protein synthesis and ribosomal content in R6/1 mouse striatum. In conclusion, our results indicate that dysregulation of protein synthesis is involved in mutant huntingtin-induced striatal neuron dysfunction. |
Note: | Versió postprint del document publicat a: https://doi.org/10.1093/brain/awz230 |
It is part of: | Brain, 2019, vol. 142, num. 10, p. 3158-3175 |
URI: | http://hdl.handle.net/2445/184510 |
Related resource: | https://doi.org/10.1093/brain/awz230 |
ISSN: | 0006-8950 |
Appears in Collections: | Articles publicats en revistes (Institut de Neurociències (UBNeuro)) Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) Articles publicats en revistes (Biomedicina) |
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