Reducing histone acetylation rescues cognitive deficits in a mouse model of Fragile X syndrome.
Reducing histone acetylation rescues cognitive deficits in a mouse model of Fragile X syndrome.
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DOI：
10.1038/s41467-018-04869-3
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发表时间：
2018-06-27
影响因子：
16.6
通讯作者：
Zhao X
中科院分区：
文献类型：
--
作者：
Li Y;Stockton ME;Eisinger BE;Zhao Y;Miller JL;Bhuiyan I;Gao Y;Wu Z;Peng J;Zhao X
脆性X综合征（FXS）是最常见的遗传性智力残疾，由脆性X智力低下蛋白（FMRP）的缺失引起。患有FXS的患者患有终身认知障碍，但FMRP在成人大脑中的功能以及FXS中与年龄相关的认知下降的潜在机制尚未完全了解。在这里，我们报告说，FMRP的损失导致增加组蛋白乙酰转移酶EP300和泛素化介导的降解组蛋白去乙酰化酶HDAC1在成年海马神经干细胞（NSC）的蛋白质合成。因此，FMRP缺陷型NSC表现出组蛋白乙酰化升高和年龄相关的NSC耗竭，导致成熟成年小鼠的认知障碍。减少组蛋白乙酰化拯救成熟成年FMRP缺陷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，并为治疗成人FXS患者提供了一种潜在的新治疗策略。脆性X智力低下蛋白（FMRP）的缺失导致脆性X综合征，与认知功能障碍有关。在这里，作者表明，缺乏FMRP的小鼠表现出海马神经发生减少和认知缺陷，这可以通过减少组蛋白乙酰化来挽救。
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. Loss of fragile X mental retardation protein (FMRP) leads to fragile X syndrome, associated with cognitive dysfunction. Here the authors show that mice lacking FMRP show reduced hippocampal neurogenesis and cognitive deficits, which can be rescued by reducing histone acetylation.
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