Xinyu Zhao, PhD – Slide of the Week

Xinyu Zhao, PhD

Title: Reducing Histone Acetylation Rescues Cognitive Deficits in a Mouse Model of Fragile X Syndrome

Legend: Adult neural stem cells in mouse models of fragile X syndrome (FXS) have elevated histone acetylation, leading to reduced neurogenesis. Treatment with either Nutlin-3 or curcumin rebalances histone acetylation and rescues cognitive functions

Citation: Li Y, Stockton ME, Eisinger BE, Zhao Y, Miller JL, Bhuiyan I, Gao Y, Wu Z, Peng J, Zhao X. (2018). Reducing histone acetylation rescues cognitive deficits in a mouse model of Fragile X syndrome.  Nature Communications, 27;9(1):2494.

Abstract: Fragile X syndrome (FXS) is the most prevalent inherited intellectual disability, resulting from a loss of the 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.

About the Lab: Research in the Zhao laboratory focuses on understanding the molecular mechanisms that regulate neural stem cells and neurodevelopment with the goal of applying this knowledge for the treatment of neurological disorders and injuries. Neurodevelopmental disorders are a highly heterogeneous constellation of disorders, both in terms of etiology and clinical manifestations. Using neural stem cells as model systems, the lab is investigating the molecular mechanisms that regulate neuronal development during the postnatal period and their implications in human neurodevelopmental disorders such as Rett syndrome, autism, and fragile X syndrome.

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