Heterogeneous nuclear ribonucleoproteins (HnRNPs) are a group of ubiquitously expressed RNA-binding proteins implicated in the regulation of all aspects of nucleic acid metabolism. HnRNP K is a member of this highly versatile hnRNP family. Pathological redistribution of hnRNP K to the cytoplasm has been linked to the pathogenesis of several malignancies but, until now, has been underexplored in the context of neurodegenerative disease. Here we show hnRNP K mislocalisation in pyramidal neurons of the frontal cortex to be a novel neuropathological feature that is associated with both frontotemporal lobar degeneration and ageing. HnRNP K mislocalisation is mutually exclusive to TDP-43 and tau pathological inclusions in neurons and was not observed to colocalise with mitochondrial, autophagosomal or stress granule markers. De-repression of cryptic exons in RNA targets following TDP-43 nuclear depletion is an emerging mechanism of potential neurotoxicity in frontotemporal lobar degeneration and the mechanistically overlapping disorder amyotrophic lateral sclerosis. We silenced hnRNP K in neuronal cells to identify the transcriptomic consequences of hnRNP K nuclear depletion. Intriguingly, by performing RNA-seq analysis we find that depletion of hnRNP K induces 101 novel cryptic exon events. We validated cryptic exon inclusion in an SH-SY5Y hnRNP K knockdown and in FTLD brain exhibiting hnRNP K nuclear depletion. We, therefore, present evidence for hnRNP K mislocalisation to be associated with FTLD and for this to induce widespread changes in splicing.

异质核核糖核蛋白 (HnRNP) 是一组普遍表达的 RNA 结合蛋白，参与核酸代谢各个方面的调节。HnRNP K 是这个高度通用的 hnRNP 家族的成员。hnRNP K 向细胞质的病理学重新分布与几种恶性肿瘤的发病机制有关，但直到现在，在神经退行性疾病的背景下仍未得到充分探索。在这里，我们显示额叶皮层锥体神经元中的 hnRNP K 错误定位是一种新的神经病理学特征，与额颞叶变性和衰老有关。HnRNP K 错误定位与 TDP-43 和神经元中的 tau 病理内含物相互排斥，并且未观察到与线粒体、自噬体或应激颗粒标记共定位。TDP-43 核耗竭后 RNA 靶标中隐蔽外显子的去抑制是额颞叶变性和机械重叠疾病肌萎缩性侧索硬化症潜在神经毒性的新兴机制。我们沉默了神经元细胞中的 hnRNP K，以确定 hnRNP K 核耗竭的转录组学后果。有趣的是，通过执行 RNA-seq 分析，我们发现 hnRNP K 的耗尽诱导了 101 个新的隐蔽外显子事件。我们在 SH-SY5Y hnRNP K 敲低和表现出 hnRNP K 核耗竭的 FTLD 大脑中验证了隐含的外显子包含。因此，我们提供了 hnRNP K 错误定位与 FTLD 相关的证据，并为此引起了剪接的广泛变化。