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New clue to ALS and FTD: Faulty protein disrupts brain's 'brake' system

Findings point to promising drug that restores neuron balance and may slow disease progression

• Protein TDP-43 malfunctions and disrupts the normal splicing of the KCNQ2 gene
• Mis-splicing of the gene causes neurons to fire too much, too easily in ALS and FTD
• Study authors developed a new drug, which calmed overactive ALS neurons

CHICAGO --- A new Northwestern University study using patient nervous tissue and lab-grown human neurons has uncovered how a key disease protein, TDP-43, drives overactive nerve cells in the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

The findings not only explain a long-standing mystery of why nerve cells overfire in ALS and FTD but also highlight a promising new drug to slow or prevent disease progression.

The findings will be published Oct. 31 in Nature Neuroscience.

ALS, which attacks the spinal cord's motor neurons and causes progressive weakness and muscle atrophy, affects about 350,000 people worldwide. FTD leads to atrophy in the brain's frontal and temporal lobes, which are known to control personality, behavior and language. It is estimated that anywhere from 1.2 to 1.8 million people worldwide are living with some form of FTD.

While ALS and FTD are quite different, a consistent but poorly explained feature of both diseases is neuronal hyperexcitability in which neurons fire too much and too easily. Previous research has found nearly all ALS and as many as half of FTD cases share one hallmark problem: the protein TDP-43 moves from its normal location, the nucleus, to the cytoplasm, and disrupts normal cellular function.

The new study found that when TDP-43 malfunctions, it disrupts the normal splicing of the KCNQ2 channel, which can be thought of as a "brake" that typically keeps neurons from firing too much. Without this brake, neurons become electrically overactive (neuronal hyperexcitability). ALS patients exhibiting hyperexcitability have been shown to have an increased risk of mortality, underscoring its clinical significance.

The study authors designed, developed and tested a gene-targeting drug that the study found can fix this error in lab-grown human neurons, which restores balance and reduces overactivity. The drug is known as an antisense oligonucleotide (ASO), which, once clinically validated and approved, would be delivered via direct injection into a patient's central nervous system, similar to an epidural.

"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 corresponding author Evangelos Kiskinis, associate professor of neuroscience and neurology in the division of neuromuscular disease 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 scientists studied patient and lab-grown neurons as well as postmortem ALS and FTD brain and spinal cord tissue. The defect they discovered is specific to humans and does not occur in mouse or rat models, Kiskinis said. Patients in the study with more severe KCNQ2 mis-splicing had earlier onset of their disease, the study found, making it a possible biomarker for prognosis or treatment response, Kiskinis said.

"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' team is currently working to develop a biomarker test based on the identification of this mis-spliced KCNQ2 event that could lead to earlier diagnosis.

"We are excited about moving this ASO into clinical stages," he said.

The paper is titled, "TDP-43-dependent mis-splicing of KCNQ2 triggers intrinsic neuronal hyperexcitability in ALS/FTD." Other Northwestern study authors include Northwestern University Interdepartmental Neuroscience graduate student Kelly A. Marshall, postdoctoral fellow Francesco Alessandrini and Dr. Alfred L. George, chair of the department of pharmacology.

Funding for the study was provided by the National Institute on Aging (R01NS104219) and the National Institute of Neurological Disorders and Stroke (grant NS108874), both of the National Institutes of Health, the Les Turner ALS Foundation and the New York Stem Cell Foundation.

Neurons

Credit: Evangelos Kiskinis, Northwestern University