Nature neuroscienceNov 1, 2025

TDP-43-related misprocessing of a potassium channel gene causes nerve cell overactivity in ALS and FTD

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Updated Jan 6, 2026

Abstract

TAR DNA-binding protein 43 () dysfunction is associated with mis-splicing of the gene, which regulates neuronal excitability.

Nuclear depletion and cytoplasmic aggregation of TDP-43 are common in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Mis-splicing of KCNQ2 leads to a nonfunctional voltage-gated potassium channel that severely reduces ion conductance.
This mis-spliced mRNA avoids degradation and results in protein aggregation in the endoplasmic reticulum.
Intrinsic hyperexcitability in ALS neuronal models is linked to the dysfunction of KCNQ2 caused by TDP-43 mis-splicing.
Higher phosphorylated TDP-43 levels and earlier disease onset in patients correlate with the observed splicing changes.
Splice-modulating antisense oligonucleotides can rescue hyperexcitability in neurons affected by TDP-43 depletion.

Simplified

Motor neuron hyperexcitability is a broadly observed yet poorly understood feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Nuclear depletion and cytoplasmic aggregation of the RNA splicing protein TAR DNA-binding protein 43 () are observed in most ALS and FTD patients. Here we show that TDP-43 dysfunction causes mis-splicing of , which encodes a voltage-gated potassium channel (K7.2) that regulates neuronal excitability. Using iPSC-derived neurons and postmortem ALS/FTD brain and spinal cord tissue we find widespread, disease-specific and TDP-43-specific skipping of an exon encoding the KCNQ2 pore domain. The mis-spliced mRNA escapes degradation and is translated into a nonfunctional protein with severely reduced ion conductance that aggregates in the endoplasmic reticulum and causes intrinsic hyperexcitability in ALS neuronal models. This event, which correlates with higher phosphorylated TDP-43 levels and earlier age of disease onset in patients, can be rescued by splice-modulating antisense oligonucleotides that dampen hyperexcitability in induced pluripotent stem cell cortical neurons and spinal motor neurons with TDP-43 depletion. Our work reveals that nuclear TDP-43 maintains the fidelity of KCNQ2 expression and function and provides a mechanistic link between established excitability disruption in ALS/FTD patients and TDP-43 dysfunction. v

Key numbers

60-fold

Increase in mis-spliced transcripts

Measured in -depleted neurons treated with siRNA.

0.0053

Association with earlier disease onset

P-value for the correlation between levels and age of onset.

< 0.0001

Higher phosphorylated levels

P-value indicating the relationship between mis-spliced and phosphorylation.

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Funding

Competing interests

Competing interests: P.F. is an academic founder of Trace Neuroscience, consults and is a Scientific Advisory Board member for VectorY. B.J.W. is a Scientific Advisory Board member of Quralis. K.E. is a cofounder of Q-State Biosciences, Quralis and Enclear Therapies and is currently employed at BioMarin Pharmaceuticals. J.K.W. and E.K. are academic cofounders of NuCyRNA Therapeutics; E.K. is also an academic cofounder of NeuronGrow and a Scientific Advisory Board member of Axion Biosystems, ResQ Biotech and Synapticure. Named companies were not involved in this project. The other authors declare no competing interests.

PubMed

TDP-43-related misprocessing of a potassium channel gene causes nerve cell overactivity in ALS and FTD

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