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

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, Josué Llamas Rodríguez, Ben Langmead, Jenna M. Gregory, Philip C. Wong and Jonathan P. Ling ()
Additional contact information
Irika R. Sinha: 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
Aswathy Peethambaran Mallika: Johns Hopkins University School of Medicine
Fatemeh Abbasinejad: Johns Hopkins University
Katherine E. Irwin: Johns Hopkins University School of Medicine
Anna Lourdes F. Cruz: Johns Hopkins University School of Medicine
Vania Wang: Johns Hopkins University School of Medicine
Shaelyn R. Marx: Johns Hopkins University School of Medicine
Josué Llamas Rodríguez: Johns Hopkins University School of Medicine
Ben Langmead: Johns Hopkins University
Jenna M. Gregory: University of Aberdeen
Philip C. Wong: Johns Hopkins University School of Medicine
Jonathan P. Ling: Johns Hopkins University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-62004-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62004-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-62004-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().