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Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology.

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.

SUBMITTER: Udagawa T

PROVIDER: S-EPMC3823751 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology.

Udagawa Tsuyoshi T Farny Natalie G NG Jakovcevski Mira M Kaphzan Hanoch H Alarcon Juan Marcos JM Anilkumar Shobha S Ivshina Maria M Hurt Jessica A JA Nagaoka Kentaro K Nalavadi Vijayalaxmi C VC Lorenz Lori J LJ Bassell Gary J GJ Akbarian Schahram S Chattarji Sumantra S Klann Eric E Richter Joel D JD

Nature medicine 20131020 11

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 w ...[more]

PMID: 24141422

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Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology.

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Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology.

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