Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology

Tsuyoshi Udagawa, Natalie G. Farny, Mira Jakovcevski, Hanoch Kaphzan, Juan Marcos Alarcon, Shobha Anilkumar, Maria Ivshina, Jessica A. Hurt, Kentaro Nagaoka, Vijayalaxmi C. Nalavadi, Lori J. Lorenz, Gary J. Bassell, Schahram Akbarian, Sumantra Chattarji, Eric Klann, Joel D. Richter

Research output: Contribution to journalArticle

Abstract

Fragile X syndrome (FXS), the most common cause of inherited mental retardation and autism, is caused by transcriptional silencing of FMR1, which encodes the translational repressor fragile X mental retardation protein (FMRP). FMRP and cytoplasmic polyadenylation element-binding protein (CPEB), an activator of translation, are present in neuronal dendrites, are predicted to bind many of the same mRNAs and may mediate a translational homeostasis that, when imbalanced, results in FXS. Consistent with this possibility, Fmr1-/y; Cpeb1-/-double-knockout mice displayed amelioration of biochemical, morphological, electrophysiological and behavioral phenotypes associated with FXS. Acute depletion of CPEB1 in the hippocampus of adult Fmr1-/y mice rescued working memory deficits, demonstrating reversal of this FXS phenotype. Finally, we find that FMRP and CPEB1 balance translation at the level of polypeptide elongation. Our results suggest that disruption of translational homeostasis is causal for FXS and that the maintenance of this homeostasis by FMRP and CPEB1 is necessary for normal neurologic function.

Original languageEnglish (US)
Pages (from-to)1473-1477
Number of pages5
JournalNature Medicine
Volume19
Issue number11
DOIs
StatePublished - Nov 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Udagawa, T., Farny, N. G., Jakovcevski, M., Kaphzan, H., Alarcon, J. M., Anilkumar, S., Ivshina, M., Hurt, J. A., Nagaoka, K., Nalavadi, V. C., Lorenz, L. J., Bassell, G. J., Akbarian, S., Chattarji, S., Klann, E., & Richter, J. D. (2013). Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nature Medicine, 19(11), 1473-1477. https://doi.org/10.1038/nm.3353