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Characterising the RNA-binding protein atlas of the mammalian brain uncovers RBM5 misregulation in mouse models of Huntington’s disease

Authors :
Meeli Mullari
Nicolas Fossat
Niels H. Skotte
Andrea Asenjo-Martinez
David T. Humphreys
Jens Bukh
Agnete Kirkeby
Troels K. H. Scheel
Michael L. Nielsen
Source :
Nature Communications, Vol 14, Iss 1, Pp 1-20 (2023)
Publication Year :
2023
Publisher :
Nature Portfolio, 2023.

Abstract

Abstract RNA-binding proteins (RBPs) are key players regulating RNA processing and are associated with disorders ranging from cancer to neurodegeneration. Here, we present a proteomics workflow for large-scale identification of RBPs and their RNA-binding regions in the mammalian brain identifying 526 RBPs. Analysing brain tissue from males of the Huntington’s disease (HD) R6/2 mouse model uncovered differential RNA-binding of the alternative splicing regulator RBM5. Combining several omics workflows, we show that RBM5 binds differentially to transcripts enriched in pathways of neurodegeneration in R6/2 brain tissue. We further find these transcripts to undergo changes in splicing and demonstrate that RBM5 directly regulates these changes in human neurons derived from embryonic stem cells. Finally, we reveal that RBM5 interacts differently with several known huntingtin interactors and components of huntingtin aggregates. Collectively, we demonstrate the applicability of our method for capturing RNA interactor dynamics in the contexts of tissue and disease.

Subjects

Subjects :
Science

Details

Language :
English
ISSN :
20411723
Volume :
14
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.f7bee72a0c145a5ad5d646db7ed76f4
Document Type :
article
Full Text :
https://doi.org/10.1038/s41467-023-39936-x