In a study published in the journal Cell, researchers have identified the molecular mechanism behind neuron death in motor neuron disease and a common form of frontotemporal dementia.
The researchers from the University of Cambridge, UK, and University of Toronto, Canada, also identify potential therapeutic targets for motor neuron disease and dementia, both currently incurable diseases.
Motor neuron disease is:
- A progressive and terminal disease that damages the function of nerves and muscle; and
- It effects around 5,000.
Frontotemporal dementia is a form of dementia that causes changes in:
- Personality and behaviour; and
- Language difficulties.
A common characteristic of both diseases is the build-up of clumps of misfolded RNA-binding proteins, including a protein called FUS, in the brain and spinal cord. This leads to the death of neurons, stopping them from communicating with each other and from reaching the muscles.
In both motor neuron disease and Frontotemporal dementia, the proteins become permanently fixed as dense gels, trapping the RNA and making it unavailable for use, damaging nerve cells by blocking their ability to make the proteins needed for synaptic function and leading to the death of neurons in the brain and spinal cord.
Dr Giovanna Lalli, from Wellcome’s Neuroscience and Mental Health team, said: “Motor neurone disease and frontotemporal dementia are devastating diseases that affect thousands of people across the UK, resulting in severe damage to the brain and spinal cord. By bringing together an interdisciplinary team of researchers, this study provides important new insights into a fundamental process underlying neurodegeneration.”
The research findings
Researchers used human cells that resembled neurons to investigate how the change in FUS from a liquid to a gel process is regulated. They found that this process was reversible and was tightly controlled by enzymes which chemically alter FUS, making it able or unable to form droplets and gels.
This research provides new ideas and tools to look for 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.
Professor Peter St George-Hyslop, University of Cambridge, said “This was a very exciting set of experiments where we were able to apply 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. 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”.