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Reducing histone acetylation rescues cognitive deficits in a mouse model of Fragile X syndrome.


ABSTRACT: Fragile X syndrome (FXS) is the most prevalent inherited intellectual disability, resulting from a loss of fragile X mental retardation protein (FMRP). Patients with FXS suffer lifelong cognitive disabilities, but the function of FMRP in the adult brain and the mechanism underlying age-related cognitive decline in FXS is not fully understood. Here, we report that a loss of FMRP results in increased protein synthesis of histone acetyltransferase EP300 and ubiquitination-mediated degradation of histone deacetylase HDAC1 in adult hippocampal neural stem cells (NSCs). Consequently, FMRP-deficient NSCs exhibit elevated histone acetylation and age-related NSC depletion, leading to cognitive impairment in mature adult mice. Reducing histone acetylation rescues both neurogenesis and cognitive deficits in mature adult FMRP-deficient mice. Our work reveals a role for FMRP and histone acetylation in cognition and presents a potential novel therapeutic strategy for treating adult FXS patients.

SUBMITTER: Li Y 

PROVIDER: S-EPMC6021376 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Reducing histone acetylation rescues cognitive deficits in a mouse model of Fragile X syndrome.

Li Yue Y   Stockton Michael E ME   Eisinger Brian E BE   Zhao Yinghua Y   Miller Jessica L JL   Bhuiyan Ismat I   Gao Yu Y   Wu Zhiping Z   Peng Junmin J   Zhao Xinyu X  

Nature communications 20180627 1


Fragile X syndrome (FXS) is the most prevalent inherited intellectual disability, resulting from a loss of fragile X mental retardation protein (FMRP). Patients with FXS suffer lifelong cognitive disabilities, but the function of FMRP in the adult brain and the mechanism underlying age-related cognitive decline in FXS is not fully understood. Here, we report that a loss of FMRP results in increased protein synthesis of histone acetyltransferase EP300 and ubiquitination-mediated degradation of hi  ...[more]

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