A recent study from Northwestern University has identified how a malfunctioning protein, TDP-43, contributes to the overactivity of nerve cells in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The research used both patient nervous tissue and lab-grown human neurons to investigate the underlying mechanisms of these neurodegenerative diseases.
The study found that when TDP-43 does not function properly, it interferes with the normal splicing of the KCNQ2 gene. This gene is responsible for producing a channel that acts as a "brake" on neuron activity. Without this brake, neurons become overly active—a condition known as neuronal hyperexcitability—which is observed in nearly all ALS cases and about half of FTD cases. Previous studies have shown that patients with ALS who exhibit hyperexcitability are at greater risk for earlier mortality.
To address this problem, researchers developed an antisense oligonucleotide (ASO) drug designed to correct the splicing error in KCNQ2. In experiments using lab-grown human neurons, this drug was able to restore normal activity levels by calming overactive neurons. The treatment would be administered via direct injection into the central nervous system if it advances to clinical use.
“By fixing the KCNQ2 splicing error with the ASO drug, we were able to calm overactive neurons, and restoring neuronal activity could potentially slow disease progression,” said Evangelos Kiskinis, associate professor of neuroscience and neurology at Northwestern University Feinberg School of Medicine. “I’m thrilled we’ve finally solved a long-standing mystery of why nerve cells in ALS/FTD are overactive and stressed even before they die.”
The defect identified by the team appears specific to humans and does not occur in mouse or rat models. The severity of KCNQ2 mis-splicing also correlated with earlier onset of disease among patients studied, suggesting its potential as a biomarker for prognosis or treatment response.
“Our work connects two central features of the disease — TDP-43 pathology and hyperexcitability — into a single mechanistic pathway,” Kiskinis said. “It also points to an exciting new therapeutic target.”
Kiskinis' group is now working on developing a biomarker test based on this mis-spliced event for earlier diagnosis and plans to move their ASO therapy into clinical stages.
Other contributors from Northwestern include graduate student Kelly A. Marshall, postdoctoral fellow Francesco Alessandrini, and Dr. Alfred L. George, chair of pharmacology at Feinberg School of Medicine.
Funding for this research came from grants provided by the National Institute on Aging (R01NS104219), National Institute of Neurological Disorders and Stroke (NS108874), Les Turner ALS Foundation, and New York Stem Cell Foundation.
The full findings will be published October 31 in Nature Neuroscience.