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

Autor: Bampton A; The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK.; Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK., Gatt A; The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK.; Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK., Humphrey J; Icahn School of Medicine at Mount Sinai, New York, NY, USA., Cappelli S; International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, 34149, Trieste, Italy., Bhattacharya D; The Firc Institute of Molecular Oncology Foundation (IFOM), Milan, Italy., Foti S; The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK.; Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK., Brown AL; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK., Asi Y; The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK.; Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK., Low YH; The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK.; Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK.; Duke-NUS Medical School, Singapore, Singapore., Foiani M; The Firc Institute of Molecular Oncology Foundation (IFOM), Milan, Italy.; University of Milan, Milan, Italy., Raj T; Icahn School of Medicine at Mount Sinai, New York, NY, USA., Buratti E; International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, 34149, Trieste, Italy., Fratta P; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK. p.fratta@ucl.ac.uk., Lashley T; The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK. T.Lashley@ucl.ac.uk.; Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK. T.Lashley@ucl.ac.uk.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2021 Oct; Vol. 142 (4), pp. 609-627. Date of Electronic Publication: 2021 Jul 18.
DOI: 10.1007/s00401-021-02340-0
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
Externí odkaz: