Increased translation as a novel pathogenic mechanism in Huntington's disease

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...

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Bibliographic Details
Authors: 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
Format: article
Status:Versión aceptada para publicación
Publication Date:2019
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/184510
Online Access:https://hdl.handle.net/2445/184510
Access Level:Open access
Keyword:Corea de Huntington
Proteïnes
Depressió psíquica
Síntesi proteica
Huntington's chorea
Proteins
Mental depression
Protein synthesis
Description
Summary: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.

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