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

Author

Listed:
  • Yue Li

    (University of Wisconsin-Madison
    University of Wisconsin-Madison
    Tianjin University of Traditional Chinese Medicine)

  • Michael E. Stockton

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Brian E. Eisinger

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Yinghua Zhao

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Jessica L. Miller

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Ismat Bhuiyan

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Yu Gao

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Zhiping Wu

    (St. Jude Children’s Research Hospital)

  • Junmin Peng

    (St. Jude Children’s Research Hospital)

  • Xinyu Zhao

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

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.

Suggested Citation

  • Yue Li & Michael E. Stockton & Brian E. Eisinger & Yinghua Zhao & Jessica L. Miller & Ismat Bhuiyan & Yu Gao & Zhiping Wu & Junmin Peng & Xinyu Zhao, 2018. "Reducing histone acetylation rescues cognitive deficits in a mouse model of Fragile X syndrome," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04869-3
    DOI: 10.1038/s41467-018-04869-3
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    Cited by:

    1. Yu Guo & Minjie Shen & Qiping Dong & Natasha M. Méndez-Albelo & Sabrina X. Huang & Carissa L. Sirois & Jonathan Le & Meng Li & Ezra D. Jarzembowski & Keegan A. Schoeller & Michael E. Stockton & Vaness, 2023. "Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway," Nature Communications, Nature, vol. 14(1), pages 1-23, December.

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