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 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. Competing Interest Statement PF, MJK and OGW have filed a patent application relating to the use of antisense oligonucleotides for the correction of cryptic splicing in UNC13A. PF is founder, advisor, and holds shares in Trace Neuroscience Inc. MJK performs consulting for and holds shares in Trace Neuroscience Inc. PH performs consulting for Trace Neuroscience Inc.