bioRxiv : the preprint server for biologySep 15, 2025

Hidden errors in genes controlling nerve signal and membrane activity connect TDP-43 loss to nerve cell problems

Alzheimers & Treatments Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 19, 2026

Abstract

TDP-43 reduction in human stem cell-derived neurons leads to impaired excitability and synaptic transmission due to cryptic splicing of critical genes.

The study identifies new TDP-43 splicing targets important for neuronal membrane excitability and synaptic function.
Reduction of TDP-43 results in the downregulation of these splicing targets, which is associated with neuronal dysfunction.
In postmortem FTD brains, cryptic splicing events occur selectively in neurons exhibiting TDP-43 pathology.
Using antisense oligonucleotides to suppress individual cryptic splicing events partially restores neuronal function.
Combined targeting of multiple splicing events nearly fully rescues synaptic deficits caused by TDP-43 loss.

Simplified

TDP-43 pathology is a defining pathological hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major feature of TDP-43 pathology is its nuclear depletion, leading to the aberrant inclusion of cryptic exons during RNA splicing.andhave emerged as prominent TDP-43 splicing targets, but the broader impact of TDP-43-dependent cryptic splicing on neuronal function remains unclear. Here, we report new TDP-43 splicing targets critical for membrane excitability and synaptic function, including,,and. Using human stem cell-derived neurons, we show that TDP-43 reduction induces cryptic splicing and downregulation of these genes, resulting in impaired excitability and synaptic transmission. In postmortem brains from patients with FTD, these cryptic splicing events occur selectively in neurons with TDP-43 pathology. Importantly, suppressing individual cryptic splicing events using antisense oligonucleotides partially restores neuronal function, and combined targeting almost fully rescues the synaptic deficit caused by TDP-43 loss. Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD. STMN2UNC13A KALRN RAP1GAP SYT7KCNQ2

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Competing interests

Competing Interests A.D.G. is a scientific founder of Maze Therapeutics, Trace Neuroscience, and Lyterian Therapeutics. S.M., R.D.M., G.M., and E.M.G. are employees of Trace Neuroscience. Stanford University has filed a provisional patent on ASOs targeting some of the cryptic splicing events described in this manuscript.

PubMed

Hidden errors in genes controlling nerve signal and membrane activity connect TDP-43 loss to nerve cell problems

Abstract

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Funding

Competing interests

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Abstract

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