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bioRxiv · 10.1101/2025.07.09.664014

Nonsense-mediated decay masks cryptic splicing events caused by TDP-43 loss

Zeng, Y.·Sianto, O.·Lovchykova, A.·Liu, C.·Akiyama, T.·Petrucelli, L.·Gitler, A. D.
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Abstract

In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is lost from the nucleus, leading to cryptic exon inclusion events in dozens of neuronal genes. Here, we show that many cryptic splicing events have been missed by standard RNA-sequencing analyses because they are substrates for nonsense-mediated decay. By inhibiting nonsense-mediated decay in neurons we unmask hundreds of novel cryptic splicing events caused by TDP-43 depletion, providing a new picture to TDP-43 loss of function in neurons.

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Zeng, Y., Sianto, O., Lovchykova, A., Liu, C., Akiyama, T., Petrucelli, L., Gitler, A. D.. 2025-07-09. Nonsense-mediated decay masks cryptic splicing events caused by TDP-43 loss. https://doi.org/10.1101/2025.07.09.664014

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