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

Author

Listed:
  • Hannah E. Salapa

    (University of Saskatchewan
    University of Saskatchewan
    University of Saskatchewan)

  • Patricia A. Thibault

    (University of Saskatchewan
    University of Saskatchewan
    University of Saskatchewan)

  • Cole D. Libner

    (University of Saskatchewan
    University of Saskatchewan
    University of Saskatchewan)

  • Yulian Ding

    (University of Saskatchewan
    University of Saskatchewan)

  • Joseph-Patrick W. E. Clarke

    (University of Saskatchewan
    University of Saskatchewan
    University of Saskatchewan)

  • Connor Denomy

    (University of Saskatchewan)

  • Catherine Hutchinson

    (University of Saskatchewan
    University of Saskatchewan
    University of Saskatchewan)

  • Hashim M. Abidullah

    (University of Saskatchewan
    University of Saskatchewan
    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
    University of Saskatchewan
    University of Saskatchewan
    University of Saskatchewan)

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.

Suggested Citation

  • 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, 2024. "hnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS)," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44658-1
    DOI: 10.1038/s41467-023-44658-1
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