Although amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). are very different diseases, they have something in common: overexcited neurons. Neurons send crucial signals that allow us to think and move, but that signaling can go awry in ALS and FTD, and neurons may start firing too often and too easily. But researchers have now revealed how a particular molecule that has been implicated in both disorders called TDP-43 can lead to overactivity in neurons. This work, which was reported in Nature Neuroscience, may open up new treatment options for both ALS and FTD.
In ALS, the motor neurons that control movement begin to die, leading to weakness and muscle atrophy. It is usually fatal. FTD causes neurons in the frontal and temporal lobes of the brain to die; these areas are known to relate to behavior, personality, and language.
Though these diseases are quite different, in about half of FTD cases and practically every case of ALS, the TDP-43 protein moves away from the place in the cell that it normally resides: the nucleus, and goes into the cytoplasm instead. Cellular function is then disrupted.
This study analyzed patient samples and neurons grown in culture to shown that the malfunction of TDP-43 interferes with a modification of another protein known as the KCNQ2 channel. This channel normally prevents neurons from becoming overactive. But as this function is disrupted, neurons become hyperexcitable.
The study authors also created and tested a molecule known as an antisense oligonucleotide (ASO) that can target aberrant gene transcripts. This method was shown to reduce hyperexcitability in neurons grown in culture. While a lot more work will be needed before this can be translated into a drug that will work in patients, it is a huge step forward for devastating diseases with few effective treatments.
The investigators also found that this mechanism is not at work in rodent models, and is specific to human neurons.
"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 study author Evangelos Kiskinis, an associate professor 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 study also showed that more severe defects in KCNQ2 led to cases of disease with earlier onsets. The investigators are now developing a test that can ascertain KCNQ2 defects and could diagnose affected individuals sooner.
"We are excited about moving this ASO into clinical stages," added Kiskinis.
Sources: Northwestern University, Nature Neuroscience
