Reducing histone acetylation rescues cognitive deficits in a mouse model of Fragile X syndrome.
Yue LiMichael E StocktonBrian E EisingerYinghua ZhaoJessica L MillerIsmat BhuiyanYu GaoZhiping WuJunmin PengXinyu ZhaoPublished in: Nature communications (2018)
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.
Keyphrases
- histone deacetylase
- cognitive decline
- mouse model
- dna methylation
- intellectual disability
- mild cognitive impairment
- neural stem cells
- cognitive impairment
- end stage renal disease
- autism spectrum disorder
- childhood cancer
- chronic kidney disease
- newly diagnosed
- ejection fraction
- case report
- cerebral ischemia
- young adults
- peritoneal dialysis
- skeletal muscle
- prognostic factors
- high fat diet induced
- insulin resistance
- wild type