hnRNP A1 dysfunction in oligodendrocytes contributes to the pathogenesis of multiple sclerosis
hnRNP A1 dysfunction in oligodendrocytes contributes to the pathogenesis of multiple sclerosis
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DOI：
10.1002/glia.24300
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发表时间：
2022-11-16
期刊：
影响因子：
6.2
通讯作者：
Levin, Michael C.
中科院分区：
文献类型：
--
作者：
Jahan-Abad, Ali Jahanbazi;Salapa, Hannah E.;Levin, Michael C.
少突胶质细胞（OL）损伤和死亡是多发性硬化（MS）病理学的突出特征，但导致OL损失的机制尚未完全了解。功能失调的RNA结合蛋白（RBP），核质的错误定位和表达改变的特点，已被证明会导致细胞损失的神经系统疾病，包括在MS。由于我们以前观察到，RBP异质核核糖核蛋白A1（hnRNP A1）在MS的神经元功能失调，我们假设，它也可能有助于OL病理MS和相关模型。我们发现hnRNP A1功能障碍是MS脑中OL的特征。这些发现在MS的实验性自身免疫性脑脊髓炎（EAE）小鼠模型中得到了概括，其中hnRNP A1功能障碍是OL的特征，包括少突胶质细胞前体细胞和成熟OL，其中hnRNP A1功能障碍与脱髓鞘相关。我们还发现hnRNP A1功能障碍是由IFN γ诱导的，表明炎症影响hnRNP A1功能。为了充分理解hnRNP A1功能障碍对OL的影响，我们进行了hnRNP A1的siRNA敲除，然后进行RNA测序。RNA测序检测到超过4000个差异表达的转录本，揭示了RNA代谢、细胞形态和程序性细胞死亡途径的改变。我们证实hnRNPA1敲低对OLs有害，并诱导细胞凋亡和坏死性凋亡。总之，这些数据证明了hnRNP A1在正常OL功能和生存中的关键作用，并表明MS中OL损伤和死亡的潜在机制涉及hnRNP A1功能障碍。
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 IFN gamma, 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.