APA
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Bampton, A., Gatt, A., Humphrey, J., Cappelli, S., Bhattacharya, D., Foti, S. C., … Lashley, T. (2021). HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing. Acta Neuropathologica.
Chicago/Turabian
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Bampton, A., A. Gatt, J. Humphrey, S. Cappelli, Dipanjan Bhattacharya, Sandrine C. Foti, Anna L. Brown, et al. “HnRNP K Mislocalisation Is a Novel Protein Pathology of Frontotemporal Lobar Degeneration and Ageing and Leads to Cryptic Splicing.” Acta Neuropathologica (2021).
MLA
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Bampton, A., et al. “HnRNP K Mislocalisation Is a Novel Protein Pathology of Frontotemporal Lobar Degeneration and Ageing and Leads to Cryptic Splicing.” Acta Neuropathologica, 2021.
BibTeX Click to copy
@article{a2021a,
title = {HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing},
year = {2021},
journal = {Acta Neuropathologica},
author = {Bampton, A. and Gatt, A. and Humphrey, J. and Cappelli, S. and Bhattacharya, Dipanjan and Foti, Sandrine C. and Brown, Anna L. and Asi, Y. and Low, Yi-Hua and Foiani, M. and Raj, T. and Buratti, E. and Fratta, P. and Lashley, T.}
}
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.