UNC13A splice correction rescues synaptic dysfunction induced by TDP-43 loss.

TDP-43 loss triggers a predegenerative synaptic communication breakdown despite intact neuron structure, and correcting a single UNC13A cryptic splice event rescues synaptic deficits.

• Why it matters: TDP-43 depletion is linked to widespread cryptic splicing, but its impact on synaptic function—and whether it can be therapeutically corrected—was unclear.
• What they did: The team designed splice-switching antisense oligonucleotides to fix UNC13A cryptic splicing in human cortical and spinal motor neurons and in a humanized mouse model. They then measured spontaneous and evoked vesicle release, release probability at individual synapses, and network synchrony.
• The result: UNC13A splice correction restored vesicle release, synaptic release probability, and wider network synchrony in human neurons, supporting a genetically validated therapeutic strategy for ~97% of ALS and ~50% of FTD with TDP-43 pathology.

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