Khan Muhammad I, Zhang Juan, Liu Qiang
Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences.
Neurodegenerative Disease Research Center.
Neuroreport. 2021 Jun 9;32(9):824-832. doi: 10.1097/WNR.0000000000001662.
Amyloid precursor protein (APP) is a transmembrane protein that plays a crucial role in the production of amyloid-β peptides. Any disruption in APP protein production, its mRNA decay rate or processing may result in abnormal production of amyloid-β peptides and subsequent development of protein aggregation diseases. Therefore, the equilibrium is crucial for neuronal function. An association study of heterogeneous nuclear ribonucleoprotein (hnRNP)-F and hnRNP H1 with APP was carried out in Neuro-2a (N2a) cells. In the present study, we found that hnRNP F and hnRNP H1 were significantly upregulated in the hippocampus of APP/PS1 mice. The changes in APP expression were positively associated with hnRNP F and hnRNP H1 when hnRNP F and hnRNP H1 were depleted or increased in N2a cells. Importantly, cross-linked RNA immunoprecipitation demonstrated binding affinities of hnRNP F and hnRNP H1 for App mRNA. Mechanistically, mRNA stability assay revealed that overexpression of hnRNP F or hnRNP H1 increases the APP level by stabilizing App mRNA half-life, implying that levels of hnRNP F and hnRNP H1 can change the production of APP. Further understanding of the regulatory mechanism of APP expression in association with hnRNP F and hnRNP H1 would provide insights into the mechanism underlying the maintenance of brain health and cognition. This study provides a theoretical basis for the development of hnRNP-stabilizing compounds to regulate APP.
淀粉样前体蛋白（APP）是一种跨膜蛋白，在淀粉样β肽的产生过程中起着关键作用。APP蛋白产生、其mRNA衰减率或加工过程中的任何干扰都可能导致淀粉样β肽的异常产生以及随后蛋白质聚集疾病的发展。因此，这种平衡对神经元功能至关重要。在Neuro-2a（N2a）细胞中进行了异质性核糖核蛋白（hnRNP）-F和hnRNP H1与APP的关联研究。在本研究中，我们发现APP/PS1小鼠海马体中的hnRNP F和hnRNP H1显著上调。当N2a细胞中的hnRNP F和hnRNP H1被耗尽或增加时，APP表达的变化与hnRNP F和hnRNP H1呈正相关。重要的是，交联RNA免疫沉淀证明了hnRNP F和hnRNP H1与App mRNA的结合亲和力。从机制上讲，mRNA稳定性分析表明，hnRNP F或hnRNP H1的过表达通过稳定App mRNA半衰期来增加APP水平，这意味着hnRNP F和hnRNP H1的水平可以改变APP的产生。进一步了解与hnRNP F和hnRNP H1相关的APP表达调控机制将为维持脑健康和认知的潜在机制提供见解。本研究为开发用于调节APP的hnRNP稳定化合物提供了理论基础。
