2021
DOI: 10.1007/s00401-021-02340-0
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HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing

Abstract: 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 co… Show more

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Cited by 32 publications
(49 citation statements)
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References 69 publications
(87 reference statements)
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“…A similarly positioned SNV in FBXO38 -9-1 destroyed a predicted binding site for hnRNP K ( Piva et al, 2012 ). This is consistent with a recent report demonstrating that hnRNP K depletion can lead to a widespread increase in cryptic exon inclusion, and that at least some of these cryptic exons are ordinarily silenced by hnRNP K binding within 100 nt of the 3′ intron ( Bampton et al, 2021 ).…”
Section: Pseudoexon Mutation Characteristicssupporting
confidence: 93%
“…A similarly positioned SNV in FBXO38 -9-1 destroyed a predicted binding site for hnRNP K ( Piva et al, 2012 ). This is consistent with a recent report demonstrating that hnRNP K depletion can lead to a widespread increase in cryptic exon inclusion, and that at least some of these cryptic exons are ordinarily silenced by hnRNP K binding within 100 nt of the 3′ intron ( Bampton et al, 2021 ).…”
Section: Pseudoexon Mutation Characteristicssupporting
confidence: 93%
“…HnRNP K mislocalisation in layers III and V pyramidal neurons is intriguing because these neurons are not typically associated with classical FTLD pathologies, and indeed, we previously demonstrated the mutual exclusivity of hnRNP K and TDP‐43/Tau pathologies in FTLD brain [ 1 ]. This prompted us to explore other brain regions and neuronal subtypes that may also exhibit hnRNP K mislocalisation but which are not usually implicated in neurodegeneration.…”
Section: Figurementioning
confidence: 99%
“…To determine whether hnRNP K mislocalisation in the dentate nucleus was related to mislocalisation in the cortex, we correlated our FTLD‐TDP A case‐matched scores from this cohort and our previous dataset [ 1 ]. We found a significant association ( r = 0.520, p = 0.027) between case scores ( n = 18) suggesting cases vulnerable to hnRNP K mislocalisation in one brain region are more susceptible to mislocalisation in another (Figure S1C ).…”
Section: Figurementioning
confidence: 99%
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