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Nat Commun. 2018 Jun 27;9(1):2494. doi: 10.1038/s41467-018-04869-3.

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

Author information

1
Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA.
2
Department of Neuroscience, University of Wisconsin-Madison, Madison, WI, 53705, USA.
3
Institute of Traditional Chinese Medicine Research, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.
4
Departments of Structural Biology and Developmental Neurobiology, St. Jude Proteomics Facility, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
5
Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA. Xinyu.zhao@wisc.edu.
6
Department of Neuroscience, University of Wisconsin-Madison, Madison, WI, 53705, USA. Xinyu.zhao@wisc.edu.

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.

PMID:
29950602
PMCID:
PMC6021376
DOI:
10.1038/s41467-018-04869-3
[Indexed for MEDLINE]
Free PMC Article

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