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

研究成果: Article査読

87 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1473-1477
ページ数5
ジャーナルNature Medicine
19
11
DOI
出版ステータスPublished - 2013 11
外部発表はい

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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