SFRS11 Loss Leads to Aging-Associated Cognitive Decline by Modulating LRP8 and ApoE
SFRS11 Loss Leads to Aging-Associated Cognitive Decline by Modulating LRP8 and ApoE
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SFRS11 缺失通过调节 LRP8 和 ApoE 导致与衰老相关的认知能力下降
DOI：
10.1016/j.celrep.2019.06.002
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发表时间：
2019-07-02
期刊：
影响因子：
8.8
通讯作者：
Liu, Qiang
中科院分区：
文献类型：
--
作者：
Raihan, Obayed;Brishti, Afrina;Liu, Qiang
RNA结合蛋白，在转录后水平的基因表达的关键调节因子，仍然在很大程度上不确定的老化和相关的认知功能减退。在这里，我们报告说，SFRS11的水平在老年人大脑的前额叶皮层（PFC）大幅下降。值得注意的是，PFC中SFRS11缺陷的小鼠表现出学习和记忆受损。我们证明SFRS11直接结合LRP 8 mRNA的3' UTR，以及apoE mRNA的第三外显子，导致这些mRNA的稳定，最终使JNK信号失活。重要的是，LRP 8和apoE的恢复减少了JNK信号传导，这在SFRS 11缺陷细胞中显著增强。此外，LRP 8和apoE拯救由SFRS 11损失诱导的衰老样表型。我们的研究结果表明，PFC中SFRS11的年龄依赖性损失降低了apoE和LRP 8的水平，导致JNK通路的激活，最终影响认知缺陷。
RNA binding proteins, the key regulators in gene expression at the posttranscriptional level, remain largely uncharacterized with respect to aging and relevant cognitive deterioration. Here, we report that the levels of SFRS11 are substantially decreased in the prefrontal cortex (PFC) of aged brains. Notably, mice with SFRS11 deficiency in the PFC show impaired learning and memory. We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling. Importantly, restoration of LRP8 and apoE reduces JNK signaling that is significantly enhanced in SFRS11-deficient cells. In addition, LRP8 and apoE rescue aging-like phenotypes induced by SFRS11 loss. Our findings demonstrate that age-dependent loss of SFRS11 in the PFC reduces levels of apoE and LRP8, leading to activation of the JNK pathway, ultimately influencing cognitive deficits.