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

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...

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Autores principales: Bampton, Alexander, Gatt, Ariana, Humphrey, Jack, Cappelli, Sara, Bhattacharya, Dipanjan, Foti, Sandrine, Brown, Anna-Leigh, Asi, Yasmine, Low, Yi Hua, Foiani, Marco, Raj, Towfique, Buratti, Emanuele, Fratta, Pietro, Lashley, Tammaryn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423707/
https://www.ncbi.nlm.nih.gov/pubmed/34274995
http://dx.doi.org/10.1007/s00401-021-02340-0
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author Bampton, Alexander
Gatt, Ariana
Humphrey, Jack
Cappelli, Sara
Bhattacharya, Dipanjan
Foti, Sandrine
Brown, Anna-Leigh
Asi, Yasmine
Low, Yi Hua
Foiani, Marco
Raj, Towfique
Buratti, Emanuele
Fratta, Pietro
Lashley, Tammaryn
author_facet Bampton, Alexander
Gatt, Ariana
Humphrey, Jack
Cappelli, Sara
Bhattacharya, Dipanjan
Foti, Sandrine
Brown, Anna-Leigh
Asi, Yasmine
Low, Yi Hua
Foiani, Marco
Raj, Towfique
Buratti, Emanuele
Fratta, Pietro
Lashley, Tammaryn
author_sort Bampton, Alexander
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-021-02340-0.
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spelling pubmed-84237072021-09-09 HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing Bampton, Alexander Gatt, Ariana Humphrey, Jack Cappelli, Sara Bhattacharya, Dipanjan Foti, Sandrine Brown, Anna-Leigh Asi, Yasmine Low, Yi Hua Foiani, Marco Raj, Towfique Buratti, Emanuele Fratta, Pietro Lashley, Tammaryn Acta Neuropathol Original Paper 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-021-02340-0. Springer Berlin Heidelberg 2021-07-18 2021 /pmc/articles/PMC8423707/ /pubmed/34274995 http://dx.doi.org/10.1007/s00401-021-02340-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Paper
Bampton, Alexander
Gatt, Ariana
Humphrey, Jack
Cappelli, Sara
Bhattacharya, Dipanjan
Foti, Sandrine
Brown, Anna-Leigh
Asi, Yasmine
Low, Yi Hua
Foiani, Marco
Raj, Towfique
Buratti, Emanuele
Fratta, Pietro
Lashley, Tammaryn
HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing
title HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing
title_full HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing
title_fullStr HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing
title_full_unstemmed HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing
title_short HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing
title_sort hnrnp k mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423707/
https://www.ncbi.nlm.nih.gov/pubmed/34274995
http://dx.doi.org/10.1007/s00401-021-02340-0
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