Publications

2024

Keuss MJ, Harley P, Ryadnov E, Jackson RE, Zanovello M, Wilkins OG, Barattucci S, Mehta PR, Oliveira MG, Parkes JE, Sinha A, Correa-Sánchez AF, Oliver PL, Fisher EMC, Schiavo G, Shah M, Burrone J, Fratta P (2024) Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs. bioRxiv

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.