Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs
Keuss, M. J.; Harly, P.; Ryadnov, E.; Jackson, R. E.; Zanovello, M.; Wilkins, O. G.; Barattucci, S.; Mehta, P. R.; Oliveira, M. G.; Parkes, J. E.; Sinha, A.; Correa-Sanchez, A. F.; Oliver, P. L.; Fisher, E. M. C.; Schiavo, G.; Shah, M.; Burrone, J.; Fratta, P.
Show 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.
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