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Large-scale RNA-Seq mining reveals ciclopirox olamine induces TDP-43 cryptic exons

Author

Listed:
  • Irika R. Sinha

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Parker S. Sandal

    (Johns Hopkins University School of Medicine)

  • Holly Spence

    (University of Aberdeen)

  • Grace D. Burns

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Aswathy Peethambaran Mallika

    (Johns Hopkins University School of Medicine)

  • Fatemeh Abbasinejad

    (Johns Hopkins University)

  • Katherine E. Irwin

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Anna Lourdes F. Cruz

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Vania Wang

    (Johns Hopkins University School of Medicine
    Johns Hopkins University Bloomberg School of Public Health)

  • Shaelyn R. Marx

    (Johns Hopkins University School of Medicine
    University of Florida College of Medicine)

  • Josué Llamas Rodríguez

    (Johns Hopkins University School of Medicine)

  • Ben Langmead

    (Johns Hopkins University
    Johns Hopkins University)

  • Jenna M. Gregory

    (University of Aberdeen
    NHS Grampian Tissue Biorepository)

  • Philip C. Wong

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Jonathan P. Ling

    (Johns Hopkins University School of Medicine)

Abstract

Nuclear clearance and cytoplasmic aggregation of TDP-43, initially identified in ALS-FTD, are hallmark pathological features observed across a spectrum of neurodegenerative diseases. We previously found that TDP-43 loss-of-function leads to transcriptome-wide inclusion of deleterious cryptic exons, a signature detected in presymptomatic biofluids and postmortem ALS-FTD brain tissue, but the upstream mechanisms that lead to TDP-43 dysregulation remain unclear. Here, we developed a web-based resource (SnapMine) to determine the levels of TDP-43 cryptic exon inclusion across hundreds of thousands of publicly available RNA sequencing datasets. We established cryptic exon inclusion levels across a variety of human cells and tissues to provide ground truth references for future studies on TDP-43 dysregulation. We then explored studies that were entirely unrelated to TDP-43 or neurodegeneration and found that ciclopirox olamine (CPX), an FDA-approved antifungal, can trigger the inclusion of TDP-43-associated cryptic exons in a variety of mouse and human primary cells. CPX induction of cryptic exons arises from heavy metal toxicity and oxidative stress, suggesting that similar vulnerabilities could play a role in neurodegeneration. Our work demonstrates how diverse datasets can be linked through common biological features and underscores how public archives of sequencing data remain a vastly underutilized resource with tremendous potential for uncovering novel insights into complex biological mechanisms and diseases.

Suggested Citation

  • Irika R. Sinha & Parker S. Sandal & Holly Spence & Grace D. Burns & Aswathy Peethambaran Mallika & Fatemeh Abbasinejad & Katherine E. Irwin & Anna Lourdes F. Cruz & Vania Wang & Shaelyn R. Marx & Josu, 2025. "Large-scale RNA-Seq mining reveals ciclopirox olamine induces TDP-43 cryptic exons," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62004-5
    DOI: 10.1038/s41467-025-62004-5
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