Memory Decline and Its Reversal in Aging and Neurodegeneration Involve miR-183/96/182 Biogenesis
Memory Decline and Its Reversal in Aging and Neurodegeneration Involve miR-183/96/182 Biogenesis
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DOI：
10.1007/s12035-018-1314-3
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发表时间：
2019-05-01
影响因子：
5.1
通讯作者：
Mansuy, Isabelle M.
中科院分区：
文献类型：
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作者：
Jawaid, Ali;Woldemichael, Bisrat T.;Mansuy, Isabelle M.
衰老的特点是进行性记忆衰退，当与神经退行性疾病相关时，可能导致痴呆。在这里，我们在小鼠中发现，与衰老相关的记忆衰退涉及 microRNA (miRNA) 的生物发生缺陷，特别是 miR-183/96/182 簇，这是由于蛋白磷酸酶 1 (PP1) 增加和受体 SMAD (R-SMAD) 信号传导改变所致。通过在海马中过度表达 miR-183/96/182 或通过使 PP1 活性正常化的环境富集来纠正缺陷，可以恢复老年动物的记忆。 miR-183/96/182 生物发生的调节涉及神经退行性变相关的 RNA 结合蛋白 TDP-43 和 FUS。在肌萎缩侧索硬化症 (ALS) 或额颞叶变性 (FTLD) 患者的大脑中观察到 miR-183/96/182、PP1 和 R-SMAD 的类似变化，这两种神经退行性疾病均伴有 TDP-43 的病理性聚集。总体而言，这些结果确定了 miR-183/96/182、PP1、TDP-43 和 FUS 在年龄相关记忆缺陷及其逆转中的新机制联系。
Aging is characterized by progressive memory decline that can lead to dementia when associated with neurodegeneration. Here, we show in mice that aging-related memory decline involves defective biogenesis of microRNAs (miRNAs), in particular miR-183/96/182 cluster, resulting from increased protein phosphatase 1 (PP1) and altered receptor SMAD (R-SMAD) signaling. Correction of the defect by miR-183/96/182 overexpression in hippocampus or by environmental enrichment that normalizes PP1 activity restores memory in aged animals. Regulation of miR-183/96/182 biogenesis is shown to involve the neurodegeneration-related RNA-binding proteins TDP-43 and FUS. Similar alterations in miR-183/96/182, PP1, and R-SMADs are observed in the brains of patients with amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD), two neurodegenerative diseases with pathological aggregation of TDP-43. Overall, these results identify new mechanistic links between miR-183/96/182, PP1, TDP-43, and FUS in age-related memory deficits and their reversal.