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

Jordi Creus-Muncunill, Raquel Badillos-Rodríguez, Marta Garcia-Forn, Mercè Masana, Gerardo Garcia Díaz Barriga, Anna Guisado-Corcoll, Jordi Alberch, Cristina Malagelada, José M. Delgado-García, Agnès Gruart, Esther Pérez-Navarro

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish
Pages (from-to)3158-3175
Number of pages18
JournalBrain
Volume142
Issue number10
DOIs
StatePublished - 1 Oct 2019
Externally publishedYes

Keywords

  • 4E-BP1
  • 4EGI-1
  • Long-term depression
  • Ribosomal proteins
  • Striatum

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