A Northwestern University study shows that mis-splicing of the KCNQ2 gene driven by TDP-43 protein causes intrinsic neuronal hyperexcitability in ALS and FTD, tying TDP-43 pathology to a specific functional defect.

The study used patient-derived neurons, lab-grown neurons, and postmortem tissue, highlighting the human-specific nature of the defect and its absence in mouse or rat models.

In lab-grown human neurons, a targeted ASO was shown to correct the KCNQ2 mis-splicing, restore normal neuronal activity, and potentially slow disease progression.

The work links TDP-43 pathology to neuronal hyperexcitability via a single mechanistic pathway, identifying a promising therapeutic target.

The research, published in Nature Neuroscience, frames the finding with the title: TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD.

Researchers envision delivering a targeted antisense oligonucleotide (ASO) through direct CNS injection once it is clinically validated and approved.

Efforts are underway to develop biomarkers to detect the mis-spliced KCNQ2 event, with the goal of earlier diagnosis and guiding ASO clinical trials.

Greater severity of KCNQ2 mis-splicing correlated with earlier disease onset, suggesting potential use as a prognostic biomarker or treatment-response indicator.

The mis-splicing disrupts a neuronal 'brake' that normally prevents overfiring, providing a direct mechanism by which TDP-43 pathology drives hyperexcitability in ALS and FTD.