The mechanism of neuron death in motor neuron disease and frontotemporal dementia discovered.

Scientists have identified the molecular mechanism that leads to the death of neurons in amyotrophic lateral sclerosis (also known as ALS or motor neurone disease) and a common form of frontotemporal dementia.

Writing in Cell, the researchers from the University of Cambridge and University of Toronto also identify potential therapeutic targets for these currently incurable diseases.

In research funded by Wellcome, scientists used human cells that resembled neurons and neurons from frogs to investigate how the change in FUS from liquid droplets to small gels process is regulated and what makes it go awry. They found that this reversible process was tightly controlled by enzymes which chemically alter FUS making it able or unable to form droplets and gels. In frontotemporal dementia, the abnormal gelling was found to be caused by defects in the chemical modification of FUS. In motor neuron disease, it was caused by mutations in the FUS protein itself which meant it was no longer able to change form.

This research provides new ideas and tools to find ways to prevent or reverse the abnormal gelling of FUS as a treatment for these devastating diseases. Potential therapeutic targets identified by the researchers are the enzymes that regulate the chemical modification of FUS and the molecular chaperones that facilitate FUS proteins to change its form. These treatments would need to allow FUS to continue moving between safe reversible states (liquid droplets and reversible gels) but prevent FUS from dropping into the dense, irreversible gel states that cause disease.