期刊
ACTA NEUROPATHOLOGICA
卷 142, 期 4, 页码 609-627出版社
SPRINGER
DOI: 10.1007/s00401-021-02340-0
关键词
hnRNP K; Frontotemporal lobar degeneration; Frontotemporal dementia; RNA; Cryptic exons; Ageing
资金
- Wolfson Foundation
- Eisai
- Rosetree Trust
- US National Institutes of Health [NIH NIA R56-AG055824, NIA U01-AG068880]
- AriSLA (project PathensTDP)
- Future and Emerging Technology (FET) Horizon 2020 grant [964800]
- Alzheimer's Society
- NIHR biomedical research centre (BRC)
- UK Medical Research Council (MRC)
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- MRC [MR/M008606/1, MR/S006508/1]
- UK Motor Neurone Disease Association
- Rosetrees Trust
- UCLH NIHR Biomedical Research Centre
- Alzheimer's Research UK senior fellowship
- Reta Lila Weston Institute for Neurological Studies
- Medical Research Council [MR/M008606/1, MR/S006508/1] Funding Source: researchfish
- Motor Neurone Disease Association [Fratta/Apr19/893-792, Fratta/Mar19/951-795, Fratta/Jan15/946-795, Fratta/Apr19/868-791] Funding Source: researchfish
- Rosetrees Trust [M599] Funding Source: researchfish
Heterogeneous nuclear ribonucleoproteins (HnRNPs) play crucial roles in nucleic acid metabolism, with HnRNP K mislocalisation in neurodegenerative diseases such as frontotemporal lobar degeneration and aging being associated with widespread splicing changes.
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.
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