TDP-43: [GU]-ardian of the transcriptome.

Overview

1. Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD USA
2. Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD USA
3. Present Address: Allen Institute, WA Seattle, USA
4. Medical Scientist Training Program, Johns Hopkins School of Medicine, Baltimore, MD USA

Abstract

TDP-43 is a ubiquitously expressed, primarily nuclear DNA/RNA-binding protein implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). In this review, we examine the structure and regulation of TDP-43, how these features influence its localization and functional activity, and how their disruption may contribute to disease. Among TDP-43’s diverse functions, splicing repression of nonconserved RNA sequences termed cryptic exons has emerged as especially central to human disease. TDP-43 nuclear depletion and cytoplasmic aggregation are well-established pathological features in affected neurons and glia of neurodegenerative diseases, and accumulating evidence suggests that loss of TDP-43-mediated splicing repression occurs presymptomatically in disease. Advances in RNA-sequencing have enabled systematic identification of cryptic exon inclusion as a sensitive marker of TDP-43 dysfunction. Here, we synthesize current knowledge of TDP-43 biology and curate datasets from human tissues and experimental models, focusing on cryptic splicing to provide a resource for leveraging cryptic exon biology to better understand, detect, and target TDP-43 dysfunction.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE126543, at NCBI GEO; found in the resources table

Data availability

Data sharing is not applicable as no datasets were generated or analyzed in the article.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 5 MeSH terms, 1 funder, 667 references.

Cite

This paper

Sinha, I. R., Atkinson, A. L., Irwin, K. E., Ling, J. P., & Wong, P. C. (2026). TDP-43: [GU]-ardian of the transcriptome. Molecular neurodegeneration, 21(1), 34. https://doi.org/10.1186/s13024-026-00944-2

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