HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing

Alexander Bampton, Ariana Gatt, Jack Humphrey, Sara Cappelli, Dipanjan Bhattacharya, Sandrine Foti, Anna Leigh Brown, Yasmine Asi, Yi Hua Low, Marco Foiani, Towfique Raj, Emanuele Buratti, Pietro Fratta, Tammaryn Lashley

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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.

Original languageEnglish
Pages (from-to)609-627
Number of pages19
JournalActa Neuropathologica
Issue number4
StatePublished - Oct 2021


  • Ageing
  • Cryptic exons
  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • RNA
  • hnRNP K


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