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

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 <i>UNC13A</i>, leading to nonsense-mediated decay of <i>UNC13A</i> 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 <i>UNC13A</i>. Antisense oligonucleotides targeting the <i>UNC13A</i> 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.