Large-scale RNA-seq mining reveals ciclopirox triggers TDP-43 cryptic exons.
| العنوان: | Large-scale RNA-seq mining reveals ciclopirox triggers TDP-43 cryptic exons. |
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| المؤلفون: | Sinha IR; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Sandal PS; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Burns GD; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Mallika AP; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Irwin KE; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Cruz ALF; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Wang V; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.; Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA., Rodríguez JL; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Wong PC; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Ling JP; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Mar 30. Date of Electronic Publication: 2024 Mar 30. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Nuclear clearance and cytoplasmic aggregation of TDP-43 in neurons, 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 the transcriptome-wide inclusion of deleterious cryptic exons in brains and biofluids post-mortem as well as during the presymptomatic stage of ALS-FTD, but 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 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 exon occurs via 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 that public archives of sequencing data represent a vastly underutilized resource with tremendous potential for uncovering novel insights into complex biological mechanisms and diseases. |
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| معلومات مُعتمدة: | R01 NS095969 United States NS NINDS NIH HHS; R33 NS115161 United States NS NINDS NIH HHS; U01 FD008129 United States FD FDA HHS; UH3 NS115608 United States NS NINDS NIH HHS |
| تواريخ الأحداث: | Date Created: 20240408 Latest Revision: 20240425 |
| رمز التحديث: | 20240425 |
| مُعرف محوري في PubMed: | PMC10996699 |
| DOI: | 10.1101/2024.03.27.587011 |
| PMID: | 38585725 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2024.03.27.587011 |
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