Abstract：
Oligodendrocyte (OL) damage and death are prominent features of multiple sclerosis (MS) pathology, yet mechanisms contributing to OL loss are incompletely understood. Dysfunctional RNA binding proteins (RBPs), hallmarked by nucleocytoplasmic mislocalization and altered expression, have been shown to result in cell loss in neurologic diseases, including in MS. Since we previously observed that the RBP heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) was dysfunctional in neurons in MS, we hypothesized that it might also contribute to OL pathology in MS and relevant models. We discovered that hnRNP A1 dysfunction is characteristic of OLs in MS brains. These findings were recapitulated in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, where hnRNP A1 dysfunction was characteristic of OLs, including oligodendrocyte precursor cells and mature OLs in which hnRNP A1 dysfunction correlated with demyelination. We also found that hnRNP A1 dysfunction was induced by IFNγ, indicating that inflammation influences hnRNP A1 function. To fully understand the effects of hnRNP A1 dysfunction on OLs, we performed siRNA knockdown of hnRNP A1, followed by RNA sequencing. RNA sequencing detected over 4000 differentially expressed transcripts revealing alterations to RNA metabolism, cell morphology, and programmed cell death pathways. We confirmed that hnRNP A1 knockdown was detrimental to OLs and induced apoptosis and necroptosis. Together, these data demonstrate a critical role for hnRNP A1 in proper OL functioning and survival and suggest a potential mechanism of OL damage and death in MS that involves hnRNP A1 dysfunction.
摘要：
少突胶质细胞（OL）损伤和死亡是多发性硬化（MS）病理的突出特征，然而，导致OL损失的机制尚不完全清楚。功能失调的RNA结合蛋白（RBPs），以核细胞质错误定位和表达改变为标志，已被证明会导致神经系统疾病中的细胞丢失，包括在女士由于我们先前观察到RBP异质核核糖核蛋白A1（hnRNPA1）在MS的神经元中功能失调，我们假设它也可能导致MS和相关模型中的OL病理。我们发现hnRNPA1功能障碍是MS大脑中OLs的特征。这些发现在MS的实验性自身免疫性脑脊髓炎（EAE）小鼠模型中进行了概述，其中hnRNPA1功能障碍是OLs的特征，包括少突胶质前体细胞和成熟OLs，其中hnRNPA1功能障碍与脱髓鞘相关。我们还发现IFNγ诱导hnRNPA1功能障碍，表明炎症影响hnRNPA1功能。为了充分了解hnRNPA1功能障碍对OLs的影响，我们对hnRNPA1进行siRNA敲除,然后进行RNA测序.RNA测序检测到超过4000个差异表达的转录物，揭示了RNA代谢的改变，细胞形态学,和程序性细胞死亡途径。我们证实hnRNPA1敲低对OLs有害，并诱导细胞凋亡和坏死。一起,这些数据表明hnRNPA1在正常OL功能和生存中的关键作用,并提示MS中OL损伤和死亡的潜在机制,该机制涉及hnRNPA1功能障碍.
