Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA.
Department of Neuroscience, University of Wisconsin-Madison, Madison, WI, 53705, USA.
Nat Commun. 2018 Jun 27;9(1):2494. doi: 10.1038/s41467-018-04869-3.
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.
脆性 X 综合征（FXS）是最常见的遗传性智力障碍，由脆性 X 智力低下蛋白（FMRP）缺失引起。FXS 患者终生存在认知障碍，但 FMRP 在成年大脑中的功能以及 FXS 中与年龄相关的认知能力下降的机制尚未完全阐明。在这里，我们报告称，FMRP 的缺失会导致成年海马神经干细胞（NSC）中组蛋白乙酰转移酶 EP300 的蛋白质合成增加和组蛋白去乙酰化酶 HDAC1 的泛素化介导降解。因此，FMRP 缺失的 NSCs 表现出较高的组蛋白乙酰化和与年龄相关的 NSC 耗竭，导致成熟成年小鼠的认知障碍。降低组蛋白乙酰化可挽救成熟成年 FMRP 缺失小鼠的神经发生和认知缺陷。我们的工作揭示了 FMRP 和组蛋白乙酰化在认知中的作用，并为治疗成年 FXS 患者提供了一种潜在的新的治疗策略。
