Large-scale RNA-Seq mining reveals ciclopirox olamine induces TDP-43 cryptic exons
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 crypti...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62004-5 |
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| author | 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 Jonathan P. Ling |
| author_facet | 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 Jonathan P. Ling |
| author_sort | Irika R. Sinha |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-78c8a4350f4a4fd89550df129be3a467 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-78c8a4350f4a4fd89550df129be3a4672025-08-20T03:05:10ZengNature PortfolioNature Communications2041-17232025-07-0116111510.1038/s41467-025-62004-5Large-scale RNA-Seq mining reveals ciclopirox olamine induces TDP-43 cryptic exonsIrika R. Sinha0Parker S. Sandal1Holly Spence2Grace D. Burns3Aswathy Peethambaran Mallika4Fatemeh Abbasinejad5Katherine E. Irwin6Anna Lourdes F. Cruz7Vania Wang8Shaelyn R. Marx9Josué Llamas Rodríguez10Ben Langmead11Jenna M. Gregory12Philip C. Wong13Jonathan P. Ling14Department of Neuroscience, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of MedicineInstitute of Medical Sciences, University of AberdeenDepartment of Pathology, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of MedicineScientific Software Engineering Center, Johns Hopkins UniversityDepartment of Neuroscience, Johns Hopkins University School of MedicineDepartment of Neuroscience, Johns Hopkins University School of MedicineDepartment of Oncology, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of MedicineDepartment of Neuroscience, Johns Hopkins University School of MedicineKavli Neuroscience Discovery Institute, Johns Hopkins UniversityInstitute of Medical Sciences, University of AberdeenDepartment of Neuroscience, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-62004-5 |
| spellingShingle | 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 Jonathan P. Ling Large-scale RNA-Seq mining reveals ciclopirox olamine induces TDP-43 cryptic exons Nature Communications |
| title | Large-scale RNA-Seq mining reveals ciclopirox olamine induces TDP-43 cryptic exons |
| title_full | Large-scale RNA-Seq mining reveals ciclopirox olamine induces TDP-43 cryptic exons |
| title_fullStr | Large-scale RNA-Seq mining reveals ciclopirox olamine induces TDP-43 cryptic exons |
| title_full_unstemmed | Large-scale RNA-Seq mining reveals ciclopirox olamine induces TDP-43 cryptic exons |
| title_short | Large-scale RNA-Seq mining reveals ciclopirox olamine induces TDP-43 cryptic exons |
| title_sort | large scale rna seq mining reveals ciclopirox olamine induces tdp 43 cryptic exons |
| url | https://doi.org/10.1038/s41467-025-62004-5 |
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