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首页> 外文期刊>Journal of cellular physiology. >Amyloid beta induces Fmr1‐dependent translational suppression and hyposynchrony of neural activity via phosphorylation of eIF2α and eEF2
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Amyloid beta induces Fmr1‐dependent translational suppression and hyposynchrony of neural activity via phosphorylation of eIF2α and eEF2

机译：β淀粉样蛋白诱发Fmr1依赖转化抑制和hyposynchrony神经活动通过磷酸化eIF2α和eEF2

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Abstract Alzheimer's disease (AD) is the most common cause of dementia, with the accumulation of amyloid beta peptide (Aβ) being one of the main causes of the disease. Fragile X mental retardation protein (FMRP), encoded by fragile X mental retardation 1 (Fmr1), is an RNA‐binding protein that represses translation of its bound mRNAs or exerts other indirect mechanisms that result in translational suppression. Because the accumulation of Aβ has been shown to cause translational suppression resulting from the elevated cellular stress response, in this study we asked whether and how Fmr1 is involved in Aβ‐induced translational regulation. Our data first showed that the application of synthetic Aβ peptide induces the expression of Fmr1 in cultured primary neurons. We followed by showing that Fmr1 is required for Aβ‐induced translational suppression, hyposynchrony of neuronal firing activity, and loss of excitatory synapses. Mechanistically, we revealed that Fmr1 functions to repress the expression of phosphatases including protein phosphatase 2A (PP2A) and protein phosphatase 1 (PP1), leading to elevated phosphorylation of eukaryotic initiation factor 2‐α (eIF2α) and eukaryotic elongation factor 2 (eEF2), and subsequent translational suppression. Finally, our data suggest that such translational suppression is critical to Aβ‐induced hyposynchrony of firing activity, but not the loss of synapses. Altogether, our study uncovers a novel mechanism by which Aβ triggers translational suppression and we reveal the participation of Fmr1 in altered neural plasticity associated with Aβ pathology. Our study may also provide information for a better understanding of Aβ‐induced cellular stress responses in AD.
机译：抽象的阿尔茨海默病(AD)是最痴呆的常见原因,积累β淀粉样蛋白肽(β)之一疾病的主要原因。缺陷蛋白(FMRP),由脆性X染色体编码精神发育迟滞1 (Fmr1),是一个RNA绑定蛋白质,压制翻译的绑定信使rna或施加其他间接的机制导致转化抑制。积累β已被证明的原因转化抑制所引起的提升细胞应激反应,在这项研究中我们问是否以及如何Fmr1参与一个β诱导转化的监管。第一个显示的应用的合成β肽诱导Fmr1的表达培养初级神经元。这需要一个βFmr1诱导转化抑制,hyposynchrony的神经元活动的活动,以及兴奋性的损失突触。镇压的表达功能磷酸酶包括蛋白磷酸酶2 a(PP2A)和蛋白质磷酸酶1 (PP1),领先真核的磷酸化起始因子2量α(eIF2α)和真核生物延长因子2 (eEF2),随后平动抑制。表明,这种转化抑制的关键一个β诱导hyposynchrony射击活动,但不是突触的损失。总之,我们的研究揭示了一个新颖的机制抑制β触发转化我们揭示Fmr1参与改变了神经可塑性与β相关联病理为更好的理解一个β诱导细胞应激反应在广告。

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