hnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS)

Hannah E. Salapa, Patricia A. Thibault, Cole D. Libner, Yulian Ding, Joseph-Patrick W. E. Clarke, Connor Denomy, Catherine Hutchinson, Hashim M. Abidullah, S. Austin Hammond, Landon Pastushok, Frederick S. Vizeacoumar and Michael C. Levin ()
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Hannah E. Salapa: University of Saskatchewan
Patricia A. Thibault: University of Saskatchewan
Cole D. Libner: University of Saskatchewan
Yulian Ding: University of Saskatchewan
Joseph-Patrick W. E. Clarke: University of Saskatchewan
Connor Denomy: University of Saskatchewan
Catherine Hutchinson: University of Saskatchewan
Hashim M. Abidullah: University of Saskatchewan
S. Austin Hammond: University of Saskatchewan
Landon Pastushok: University of Saskatchewan
Frederick S. Vizeacoumar: University of Saskatchewan
Michael C. Levin: University of Saskatchewan

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Neurodegeneration is the primary driver of disease progression in multiple sclerosis (MS) resulting in permanent disability, creating an urgent need to discover its underlying mechanisms. Herein, we establish that dysfunction of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) results in differential of binding to RNA targets causing alternative RNA splicing, which contributes to neurodegeneration in MS and its models. Using RNAseq of MS brains, we discovered differential expression and aberrant splicing of hnRNP A1 target RNAs involved in neuronal function and RNA homeostasis. We confirmed this in vivo in experimental autoimmune encephalomyelitis employing CLIPseq specific for hnRNP A1, where hnRNP A1 differentially binds and regulates RNA, including aberrantly spliced targets identified in human samples. Additionally, dysfunctional hnRNP A1 expression in neurons caused neurite loss and identical changes in splicing, corroborating hnRNP A1 dysfunction as a cause of neurodegeneration. Collectively, these data indicate hnRNP A1 dysfunction causes altered neuronal RNA splicing, resulting in neurodegeneration in MS.

Date: 2024
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DOI: 10.1038/s41467-023-44658-1

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