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Published

Loss of TDP-43 induces synaptic dysfunction that is rescued by <em>UNC13A</em> splice-switching ASOs

Authors

Matthew J Keuss, Peter Harley, Eugeni Ryadnov, Rachel E Jackson, Matteo Zanovello, Oscar G Wilkins, Simone Barattucci, Puja R Mehta, Marcio G Oliveira, Joanna E Parkes, Aparna Sinha, Andrés F Correa-Sánchez, Peter L Oliver, Elizabeth M C Fisher, Giampietro Schiavo, Mala Shah, Juan Burrone, Pietro Fratta
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Abstract

bioRxiv [Preprint]. 2024 Jun 24:2024.06.20.599684. doi: 10.1101/2024.06.20.599684.

ABSTRACT

TDP-43 loss of function induces multiple splicing changes, including a cryptic exon in the amyotrophic lateral sclerosis and fronto-temporal lobar degeneration risk gene UNC13A, leading to nonsense-mediated decay of UNC13A transcripts and loss of protein. UNC13A is an active zone protein with an integral role in coordinating pre-synaptic function. Here, we show TDP-43 depletion induces a severe reduction in synaptic transmission, leading to an asynchronous pattern of network activity. We demonstrate that these deficits are largely driven by a single cryptic exon in UNC13A. Antisense oligonucleotides targeting the UNC13A cryptic exon robustly rescue UNC13A protein levels and restore normal synaptic function, providing a potential new therapeutic approach for ALS and other TDP-43-related disorders.

PMID:38979232 | PMC:PMC11230273 | DOI:10.1101/2024.06.20.599684