TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes

In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus of neurons in the brain and spinal cord. A key function of TDP-43 has emerged as a repressor of cryptic exon inclusion during pre-mRNA splicing, but a role for TDP-43 in other RNA-processing events remains unresolved. Here we show that loss of TDP-43 from neuronal nuclei of human brain and disease-causing mutations in TDP-43 are associated with widespread changes in alternative polyadenylation (APA). Using high-resolution polyadenylation site mapping, we comprehensively defined TDP-43-regulated APA events in human stem cell-derived neurons and found that both the strength and position of TDP-43 binding influence polyA site usage. APA events caused by loss of TDP-43 impact expression of disease-relevant genes (for example, SFPQ, NEFL and TMEM106B). These findings provide evidence that, in addition to cryptic exon inclusion, APA changes are a new facet of TDP-43 pathology.

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Publication Details

Journal
Nature Neuroscience
Published
2025-10-21
DOI
https://doi.org/10.1038/s41593-025-02049-3
Citations
19
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
26.40

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article

TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes

Dennis W. Dickson, Vidhya Bharathi, Mercedes Prudencio, Stephanie L. Rayner et al.
19 citations
Nature Neuroscience
Amyotrophic Lateral Sclerosis Research
26.40
article

TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes

Dennis W. Dickson, Vidhya Bharathi, Mercedes Prudencio, Stephanie L. Rayner, Leonard Petrucelli, Tetsuya Akiyama, Yi Zeng, Aaron D. Gitler, Caiwei Guo, Anna Calliari, Anastasiia Lovchykova, Odilia Sianto, Chang Liu
article en
19 citations

Abstract

In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus of neurons in the brain and spinal cord. A key function of TDP-43 has emerged as a repressor of cryptic exon inclusion during pre-mRNA splicing, but a role for TDP-43 in other RNA-processing events remains unresolved. Here we show that loss of TDP-43 from neuronal nuclei of human brain and disease-causing mutations in TDP-43 are associated with widespread changes in alternative polyadenylation (APA). Using high-resolution polyadenylation site mapping, we comprehensively defined TDP-43-regulated APA events in human stem cell-derived neurons and found that both the strength and position of TDP-43 binding influence polyA site usage. APA events caused by loss of TDP-43 impact expression of disease-relevant genes (for example, SFPQ, NEFL and TMEM106B). These findings provide evidence that, in addition to cryptic exon inclusion, APA changes are a new facet of TDP-43 pathology.

Nature NeuroscienceVol. 28(11)
Jacksonville College (US), Stanford Health Care (US), Chan Zuckerberg Initiative (United States) (US), Stanford Medicine (US), Mayo Clinic in Florida (US), Stanford University (US), Macquarie University (AU)
Larry L. Hillblom Foundation, Target ALS, FightMND, National Institutes of Health, Stanford Research Computing Center, Stanford University
Openalex Percentile: Top 0%
Amyotrophic Lateral Sclerosis Research
26.40
DOIOpen Access PDFOpenAlex
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