Study sheds light on motor neurone disease

Scientists have made a breakthrough in understanding what causes motor neurone disease and a common form of dementia.

Motor neurone disease is a progressive and terminal disease that damages the function of nerves and muscle, while frontotemporal dementia is a form that causes changes in personality and behaviour along with language difficulties.

A common characteristic of both conditions is the build-up of clumps of misfolded RNA-binding proteins - including a protein called FUS - in the brain and spinal cord.

These build-ups lead to the death of neurons, which stops them from communicating with each other and reaching the muscles.

Researchers from the University of Cambridge and University of Toronto studied these FUS proteins and how they change back and forth from small liquid droplets - resembling oil droplets in water - to small jelly-like gels inside nerve cells.

As the FUS protein condenses from droplets to gel, it captures RNA and transfers it to remote parts of the neuron that are involved in making connections (known as synapses) with other neurons.

Here, the protein "melts" and releases the RNA proteins, which are then used to create new proteins in the synapses.

This is essential for keeping the synapses working properly, especially during memory formation and learning.

However in those with frontotemporal dementia and motor neurone disease, the proteins become permanently stuck as abnormally dense gels, trapping the RNA and making it unavailable for use.

This damages nerve cells by blocking their ability to make the proteins needed for synaptic function and leads to the death of neurons in the brain and spinal cord.

The research, published in the journal Cell, saw the team use 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 wrong.

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.

They found that in motor neurone disease, it was caused by mutations in the FUS protein itself which meant it was no longer able to change form.

Professor Peter St George-Hyslop, of the Cambridge Institute for Medical Research, said the findings gave him "cautious optimism" that they could lead to ways of treating the conditions.

This was a very exciting set of experiments where we were able to applying cutting edge tools from physics, chemistry and neurobiology to understand how the FUS protein normally works in nerve cells, and how it goes wrong in motor neurone disease and dementia," he said.

It now opens up a new avenue of work to use this knowledge to identify ways to prevent the abnormal gelling of FUS in motor neurone disease and dementia.