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.

doi:10.1101/2024.06.20.599684

bioRxiv · 10.1101/2024.06.20.599684

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.

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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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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.. 2024-06-24. Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs. https://doi.org/10.1101/2024.06.20.599684

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