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

Meeli Mullari (), Nicolas Fossat, Niels H. Skotte, Andrea Asenjo-Martinez, David T. Humphreys, Jens Bukh, Agnete Kirkeby, Troels K. H. Scheel and Michael L. Nielsen ()
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Meeli Mullari: University of Copenhagen
Nicolas Fossat: University of Copenhagen
Niels H. Skotte: University of Copenhagen
Andrea Asenjo-Martinez: University of Copenhagen
David T. Humphreys: Victor Chang Cardiac Research Institute
Jens Bukh: University of Copenhagen
Agnete Kirkeby: University of Copenhagen
Troels K. H. Scheel: University of Copenhagen
Michael L. Nielsen: University of Copenhagen

Nature Communications, 2023, vol. 14, issue 1, 1-20

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.

Date: 2023
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DOI: 10.1038/s41467-023-39936-x

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