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

Yue Li (), Michael E. Stockton, Brian E. Eisinger, Yinghua Zhao, Jessica L. Miller, Ismat Bhuiyan, Yu Gao, Zhiping Wu, Junmin Peng and Xinyu Zhao ()
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Yue Li: University of Wisconsin-Madison
Michael E. Stockton: University of Wisconsin-Madison
Brian E. Eisinger: University of Wisconsin-Madison
Yinghua Zhao: University of Wisconsin-Madison
Jessica L. Miller: University of Wisconsin-Madison
Ismat Bhuiyan: University of Wisconsin-Madison
Yu Gao: 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

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04869-3

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