Neurodegeneration is the primary driver of disease progression in multiple sclerosis (MS) resulting in permanent disability, creating an urgent need to discover its underlying mechanisms. Herein, we establish that dysfunction of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) results in differential of binding to RNA targets causing alternative RNA splicing, which contributes to neurodegeneration in MS and its models. Using RNAseq of MS brains, we discovered differential expression and aberrant splicing of hnRNP A1 target RNAs involved in neuronal function and RNA homeostasis. We confirmed this in vivo in experimental autoimmune encephalomyelitis employing CLIPseq specific for hnRNP A1, where hnRNP A1 differentially binds and regulates RNA, including aberrantly spliced targets identified in human samples. Additionally, dysfunctional hnRNP A1 expression in neurons caused neurite loss and identical changes in splicing, corroborating hnRNP A1 dysfunction as a cause of neurodegeneration. Collectively, these data indicate hnRNP A1 dysfunction causes altered neuronal RNA splicing, resulting in neurodegeneration in MS.

神经退行性变是多发性硬化症 (MS) 疾病进展的主要驱动因素，导致永久性残疾，因此迫切需要发现其潜在机制。在此，我们确定 RNA 结合蛋白异质核核糖核蛋白 A1 (hnRNP A1) 的功能障碍会导致与 RNA 靶标的结合差异，从而导致选择性 RNA 剪接，从而导致 MS 及其模型中的神经变性。利用 MS 大脑的 RNAseq，我们发现了参与神经元功能和 RNA 稳态的 hnRNP A1 靶标 RNA 的差异表达和异常剪接。我们利用 hnRNP A1 特异性的 CLIPseq 在实验性自身免疫性脑脊髓炎体内证实了这一点，其中 hnRNP A1 差异性地结合和调节 RNA，包括在人类样本中发现的异常剪接靶标。此外，神经元中功能失调的 hnRNP A1 表达导致神经突丢失和剪接的相同变化，证实 hnRNP A1 功能障碍是神经退行性变的原因。总的来说，这些数据表明 hnRNP A1 功能障碍会导致神经元 RNA 剪接改变，从而导致 MS 中的神经变性。