Amyloid beta induces Fmr1-dependent translational suppression and hyposynchrony of neural activity via phosphorylation of eIF2α and eEF2.
Amyloid beta induces Fmr1-dependent translational suppression and hyposynchrony of neural activity via phosphorylation of eIF2α and eEF2.
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淀粉样蛋白β通过磷酸化eIF2α和eif2诱导fmr1依赖的翻译抑制和神经活动的低同步。
DOI：
10.1002/jcp.30754
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发表时间：
2022-07
影响因子：
5.6
通讯作者：
Tsai, Nien-Pei
中科院分区：
文献类型：
--
作者：
Lizarazo, Simon;Yook, Yeeun;Tsai, Nien-Pei
阿尔茨海默病（AD）是痴呆的最常见原因，淀粉样β肽（Aβ）的积累是该疾病的主要原因之一。脆性X智力低下蛋白（Fragile X mental retardation protein，FMRP）是由脆性X智力低下1（Fragile X mental retardation 1，Fmr 1）编码的一种RNA结合蛋白，可抑制其结合的mRNA的翻译或发挥其他间接机制，导致翻译抑制。由于Aβ的蓄积已被证明会导致细胞应激反应升高导致的翻译抑制，因此在本研究中，我们询问了Fmr 1是否以及如何参与Aβ诱导的翻译调节。我们的数据首次表明，应用合成的Aβ肽诱导原代培养的神经元中Fmr 1的表达。我们随后表明，Aβ诱导的翻译抑制，神经元放电活动的同步性不足和兴奋性突触的丧失需要Fmr 1。从机制上讲，我们揭示了Fmr 1的功能是抑制磷酸酶的表达，包括蛋白磷酸酶2A（PP 2A）和蛋白磷酸酶1（PP 1），导致真核起始因子2-α（eIF 2 α）和真核延伸因子2（eEF 2）的磷酸化升高，以及随后的翻译抑制。最后，我们的数据表明，这种翻译抑制对Aβ诱导的放电活动的不同步性至关重要，但不是突触的丢失。总之，我们的研究揭示了Aβ触发翻译抑制的新机制，我们揭示了Fmr 1参与与Aβ病理学相关的神经可塑性改变。我们的研究也可能为更好地理解AD中Aβ诱导的细胞应激反应提供信息。Aβ的蓄积导致由细胞应激反应升高引起的翻译抑制，但其机制尚不清楚。我们发现，脆性X智力低下蛋白（FMRP）是一种常见于自闭症谱系障碍的RNA结合蛋白，可由Aβ诱导，并导致Aβ依赖性翻译抑制和网络同步性降低。我们的研究可能为更好地了解Aβ诱导的阿尔茨海默病细胞应激反应提供信息。
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. The accumulation of Aβ causes translational suppression resulting from elevated cellular stress response but the mechanism is unclear. We showed that fragile X mental retardation protein (FMRP), an RNA‐binding protein commonly involved in autism spectrum disorders, can be induced by Aβ and contribute to Aβ‐dependent translational suppression and network hyposynchronicity. Our study may provide information for a better understanding of Aβ‐induced cellular stress responses in Alzheimer's disease.
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