Office of Saskatchewan Multiple Sclerosis Clinical Research Chair, CMSNRC (Cameco MS Neuroscience Research Center), College of Medicine, University of Saskatchewan, Saskatoon, SK, S7K 0M7, Canada.
Department of Health Sciences, University of Saskatchewan, Saskatoon, SK, S7N 5A2, Canada.
eNeuro. 2021 Nov 18;8(6). doi: 10.1523/ENEURO.0350-21.2021. Print 2021 Nov-Dec.
Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is an RNA binding protein (RBP) that is localized within neurons and plays crucial roles in RNA metabolism. Its importance in neuronal functioning is underscored from the study of its pathogenic features in many neurodegenerative diseases where neuronal hnRNP A1 is mislocalized from the nucleus to the cytoplasm resulting in loss of hnRNP A1 function. Here, we model hnRNP A1 loss-of-function by siRNA-mediated knock-down in differentiated Neuro-2a cells. Through RNA sequencing (RNA-seq) followed by gene ontology (GO) analyses, we show that hnRNP A1 is involved in important biological processes, including RNA metabolism, neuronal function, neuronal morphology, neuronal viability, and stress granule (SG) formation. We further confirmed several of these roles by showing that hnRNP A1 knock-down results in a reduction of neurite outgrowth, increase in cell cytotoxicity and changes in SG formation. In summary, these findings indicate that hnRNP A1 loss-of-function contributes to neuronal dysfunction and cell death and implicates hnRNP A1 dysfunction in the pathogenesis of neurodegenerative diseases.
异质核核糖核蛋白 A1（hnRNP A1）是一种 RNA 结合蛋白（RBP），定位于神经元内，在 RNA 代谢中发挥关键作用。许多神经退行性疾病中 hnRNP A1 的致病性特征研究强调了其在神经元功能中的重要性，在这些疾病中，神经元 hnRNP A1 从细胞核错误定位到细胞质，导致 hnRNP A1 功能丧失。在这里，我们通过 siRNA 介导的敲低在分化的 Neuro-2a 细胞中模拟 hnRNP A1 功能丧失。通过 RNA 测序（RNA-seq）和基因本体（GO）分析，我们表明 hnRNP A1 参与重要的生物学过程，包括 RNA 代谢、神经元功能、神经元形态、神经元活力和应激颗粒（SG）形成。我们通过进一步证明 hnRNP A1 敲低导致轴突生长减少、细胞毒性增加和 SG 形成变化，证实了其中的几个作用。总之，这些发现表明 hnRNP A1 功能丧失导致神经元功能障碍和细胞死亡，并暗示 hnRNP A1 功能障碍与神经退行性疾病的发病机制有关。
