Journal article
Identification of HnRNPC as a novel Tau exon 10 splicing factor using RNA antisense purification mass spectrometry
RNA biology, Vol.19(1), pp.104-116
2022
DOI: 10.1080/15476286.2021.2015175
PMCID: PMC8786334
PMID: 34965173
Abstract
Alternative splicing in Tau exon 10 generates 3 R- and 4 R-Tau proteoforms, which have equal abundance in healthy adult human brain. Aberrant alternative splicing in Tau exon 10 leads to distortion of the balanced 3 R- and 4 R-Tau expression levels, which is a causal factor to trigger toxic Tau aggregation, neuron dysfunction and patient death in a group of neurodegenerative diseases known as tauopathies. Hence, identification of regulators upstream of the Tau exon 10 splicing events are crucial to understanding pathogenic mechanisms driving tauopathies. In this study, we used RNA Antisense Purification with Mass Spectrometry (RAP-MS) analysis to identify RNA-binding proteins (RBPs) that interact with the Tau pre-mRNA near exon 10. Among the newly identified RBP candidates, we show that knockdown of hnRNPC induces Tau exon 10 skipping whereas overexpression of hnRNPC promotes Tau exon 10 inclusion. In addition, we show that hnRNPC interacts with the poly-uridine (U-tract) sequences in introns 9 and 10 of Tau pre-mRNA. Mutation of these U-tract motifs abolished binding of hnRNPC with Tau pre-mRNA fragment and blocked its impact on Tau exon 10 inclusion. These findings indicate that hnRNPC binds and utilizes these U-tract motifs located in introns 9 and 10 of Tau pre-mRNA to promote Tau exon 10 inclusion. Intriguingly, high hnRNPC expression level is associated with progressive supranuclear palsy (PSP), a sporadic tauopathy with pathological accumulation of Tau species that contain exon 10, which suggests a putative therapeutic role of hnRNPC for PSP treatment.
Details
- Title: Subtitle
- Identification of HnRNPC as a novel Tau exon 10 splicing factor using RNA antisense purification mass spectrometry
- Creators
- Sansi Xing - McMaster UniversityJane Wang - McMaster UniversityRuilin Wu - McMaster UniversityMarco M Hefti - University of IowaJohn F Crary - Neuropathology Brain Bank & Research Core, Icahn School of Medicine at Mount SinaiYu Lu - McMaster University
- Resource Type
- Journal article
- Publication Details
- RNA biology, Vol.19(1), pp.104-116
- DOI
- 10.1080/15476286.2021.2015175
- PMID
- 34965173
- PMCID
- PMC8786334
- NLM abbreviation
- RNA Biol
- ISSN
- 1547-6286
- eISSN
- 1555-8584
- Publisher
- Taylor & Francis
- Grant note
- DOI: 10.13039/501100000038, name: Natural Science and Engineering Research Council of Canada, award: RGPIN-2017-06159; name: Ontario Institute of Regenerative Medicine New Idea, award: 2019-0154; DOI: 10.13039/501100000196, name: Canada Foundation for Innovation; name: Ontario Ministry of Economic Development, Job Creation and Trade ORF-RI; name: Marta and Owen Boris Foundation; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01AG054008, R01NS095252; DOI: 10.13039/100016948, name: Tau Consortium; DOI: 10.13039/100000002, name: National Institutes of Health, award: K23NS109284
- Language
- English
- Date published
- 2022
- Academic Unit
- Pathology; Iowa Neuroscience Institute
- Record Identifier
- 9984209491202771
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