HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing.
HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing.
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DOI：
10.1007/s00401-021-02340-0
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发表时间：
2021-10
影响因子：
12.7
通讯作者：
Lashley T
中科院分区：
文献类型：
--
作者：
Bampton A;Gatt A;Humphrey J;Cappelli S;Bhattacharya D;Foti S;Brown AL;Asi Y;Low YH;Foiani M;Raj T;Buratti E;Fratta P;Lashley T
异质性核核糖核蛋白（HNRNP）是一组泛表达的RNA结合蛋白，该蛋白与核酸代谢的所有方面有关。 HNRNP K是这个广泛使用的HNRNP家族的成员。 HNRNP K为细胞质的病理重新分布与几种恶性肿瘤的发病机理有关，但到目前为止，在神经退行性疾病的背景下一直尚未逐渐倍增。在这里，我们表明额叶皮质的锥体神经元中的HNRNP K错误钙化是一种新型的神经病理学特征，与额颞Lobar变性和衰老都相关。 HNRNP K错误定位在神经元中相互排除在TDP-43和Tau病理夹杂物中，并且没有观察到与线粒体，自噬体或应力颗粒标记物共定位。 TDP-43核消耗后，RNA靶标中隐性外显子的抑制是一种新兴的机制，它是额颞叶变性中潜在的神经毒性的新机制，机械上重叠的肌萎缩性侧向硬化症。我们在神经元细胞中沉默了HNRNP K，以鉴定HNRNP K核耗竭的转录组后果。有趣的是，通过执行RNA-Seq分析，我们发现HNRNP K的耗竭诱导了101个新型的隐性外显子事件。我们验证了在SH-SY5Y HNRNP K敲低和表现出HNRNP K核耗竭的FTLD大脑中验证的神秘外显子包含。因此，我们提供了与FTLD相关的HNRNP K错误定位的证据，并为此引起广泛的剪接变化。
在线版本包含的补充材料可获得10.1007/S00401-021-02340-0。
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. The online version contains supplementary material available at 10.1007/s00401-021-02340-0.
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影响因子：
2.7
作者：
Humphrey J;Emmett W;Fratta P;Isaacs AM;Plagnol V
通讯作者：
Plagnol V
影响因子：
7.1
作者：
Davidson YS;Flood L;Robinson AC;Nihei Y;Mori K;Rollinson S;Richardson A;Benson BC;Jones M;Snowden JS;Pickering-Brown S;Haass C;Lashley T;Mann DMA
通讯作者：
Mann DMA
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
12.7
作者：
Bampton A;Gittings LM;Fratta P;Lashley T;Gatt A
通讯作者：
Gatt A
影响因子：
7.7
作者：
Attig, Jan;Mozos, Igor Ruiz de los;Ule, Jernej
通讯作者：
Ule, Jernej