UNC13A splice correction rescues synaptic dysfunction induced by TDP-43 loss
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.
Authors
- Puja R. Mehta (ORCID: https://orcid.org/0000-0002-0255-407X)
- Darija Šoltić (ORCID: https://orcid.org/0009-0000-3151-6016)
- Matteo Zanovello (ORCID: https://orcid.org/0000-0003-3343-1547)
- Fursham Hamid (ORCID: https://orcid.org/0000-0002-6846-7382)
- Dragana Ilic (ORCID: https://orcid.org/0000-0002-3725-7964)
- Alexander J. Cammack (ORCID: https://orcid.org/0000-0002-9624-9067)
- Eric M. Green (ORCID: https://orcid.org/0000-0001-7874-9482)
- Benjamin Davies (ORCID: https://orcid.org/0000-0003-3623-600X)
- Noa Lipstein (ORCID: https://orcid.org/0000-0002-0755-5899)
- Yan To Ling (ORCID: https://orcid.org/0000-0003-2443-1561)
- Peter L. Oliver (ORCID: https://orcid.org/0000-0003-3347-2461)
- Georgiana Miller (ORCID: https://orcid.org/0000-0002-9742-0049)
- Pietro Fratta (ORCID: https://orcid.org/0000-0002-8762-8188)
- Graham Duddy (ORCID: https://orcid.org/0009-0006-7834-7962)
- Joanna E. Parkes (ORCID: https://orcid.org/0000-0002-4007-240X)
- A. K. Sinha (ORCID: https://orcid.org/0000-0001-5184-1326)
- Elizabeth Fisher (ORCID: https://orcid.org/0000-0003-2850-9936)
- Simone Barattucci (ORCID: https://orcid.org/0009-0006-8380-2931)
- Juan Burrone (ORCID: https://orcid.org/0000-0003-1233-668X)
- Adrian M. Isaacs (ORCID: https://orcid.org/0000-0002-6820-5534)
- Matthew J. Keuss (ORCID: https://orcid.org/0000-0002-2628-4115)
- Giampietro Schiavo (ORCID: https://orcid.org/0000-0002-4319-8745)
- Ryan D. Morrie (ORCID: https://orcid.org/0000-0001-9227-4997)
- Oscar G. Wilkins (ORCID: https://orcid.org/0000-0002-3334-0568)
- Rebecca L. Simkin (ORCID: https://orcid.org/0000-0001-8093-2139)
- Max Z. Y. J. Chien (ORCID: https://orcid.org/0009-0001-7731-605X)
- Andrés F. Correa-Sánchez (ORCID: https://orcid.org/0000-0003-1423-3449)
- Peter Harley
- Eugeni Ryadnov
- Rachel Jackson
- Sophie Wood
- Moritz Boll
- Mala Shah
- Marcio G. Oliveira
- Maria Kowald
Publication Details
- Journal
- Nature
- Published
- 2026-11-11
- DOI
- https://doi.org/10.1038/s41586-026-11256-2
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00