HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing.
Ageing
Cryptic exons
Frontotemporal dementia
Frontotemporal lobar degeneration
RNA
hnRNP K
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
05
04
2021
accepted:
29
06
2021
revised:
28
06
2021
pubmed:
19
7
2021
medline:
19
3
2022
entrez:
18
7
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34274995
doi: 10.1007/s00401-021-02340-0
pii: 10.1007/s00401-021-02340-0
pmc: PMC8423707
doi:
Substances chimiques
Heterogeneous-Nuclear Ribonucleoprotein K
0
HNRNPK protein, human
146410-60-8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
609-627Subventions
Organisme : Medical Research Council
ID : MR/M008606/1
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R56 AG055824
Pays : United States
Organisme : Motor Neurone Disease Association
ID : FRATTA/JAN15/946-795
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S006508/1
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : U01 AG068880
Pays : United States
Organisme : Medical Research Council
ID : MR/M008606/1 & MR/S006508/1
Pays : United Kingdom
Organisme : NIH HHS
ID : R56-AG055824
Pays : United States
Organisme : NIH HHS
ID : U01-AG068880
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066514
Pays : United States
Organisme : Medical Research Council
ID : MC_PC_MR/S022708/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
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