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
Download full text from publisher
Corrections
All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62004-5. See general information about how to correct material in RePEc.
If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.
We have no bibliographic references for this item. You can help adding them by using this form .
If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.
For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .
Please note that corrections may take a couple of weeks to filter through
the various RePEc services.