UNC13A splice correction rescues synaptic dysfunction

Authors

Matthew J Keuss, Peter Harley, Eugeni Ryadnov, Rachel E Jackson, Moritz Boll, Matteo Zanovello, Oscar G Wilkins, Simone Barattucci, Dragana Ilic, Rebecca L Simkin, Max Z Y J Chien, Alexander J Cammack, Darija Šoltić, Puja R Mehta, Yan To Ling, Maria Kowald, Ryan D Morrie, Georgiana Miller, Marcio G Oliveira, Graham Duddy, Sophie Wood, Joanna E Parkes, Aparna Sinha, Andrés F Correa-Sánchez, Adrian M Isaacs, Peter L Oliver, Fursham Hamid, Eric M Green, Elizabeth M C Fisher, Benjamin Davies, Giampietro Schiavo, Mala Shah, Noa Lipstein, Juan Burrone, Pietro Fratta

Abstract

Nature. 2026 Nov 11. doi: 10.1038/s41586-026-11256-2. Online ahead of print.

ABSTRACT

TDP-43 nuclear depletion is a defining pathological feature of amyotrophic lateral sclerosis and frontotemporal dementia that induces widespread cryptic splicing defects in hundreds of transcripts^1-8. Despite this, whether TDP-43 loss affects synaptic function has remained unclear. Here we show that TDP-43 loss induces a predegenerative state in which neurons remain structurally intact but suffer a substantial breakdown in synaptic communication. Genetic correction of a single cryptic splicing event in UNC13A was sufficient to rescue these deficits. We developed splice-switching antisense oligonucleotides that correct UNC13A cryptic splicing in human cortical and spinal motor neurons and in a humanized mouse model. In human neurons this intervention restored spontaneous and evoked synaptic vesicle release, release probability at individual synapses and wider network synchrony. Together, this establishes UNC13A splice correction as a mechanistically defined and genetically validated therapeutic strategy relevant to roughly 97% of patients with amyotrophic lateral sclerosis and roughly 50% of patients with frontotemporal dementia with TDP-43 pathology.

PMID:43015463 | DOI:10.1038/s41586-026-11256-2