University of Cambridge researchers uncover new insights into motor neurone disease and common form of dementia

PUBLISHED: 10:30 27 April 2018 | UPDATED: 10:42 27 April 2018

An illustration of neuron cells

An illustration of neuron cells

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Understanding of process leading to death of nerve cells could lead to potential therapies

Professor Stephen Hawking was diagnosed with motor neurone disease in his early twenties and was given a few years to live. He died on March 14, 2018, aged 76. Picture: Andre PattendenProfessor Stephen Hawking was diagnosed with motor neurone disease in his early twenties and was given a few years to live. He died on March 14, 2018, aged 76. Picture: Andre Pattenden

University of Cambridge scientists have uncovered the process that leads to the death of nerve cells in those with motor neurone disease and a common form of dementia.

The researchers, working with others from the University of Toronto, have also identified potential therapeutic targets for the diseases, which currently have no cure.

Motor neurone disease, or amyotrophic lateral sclerosis (ALS), is a progressive, terminal disease that damages the function of nerves and muscle. Affecting up to 5,000 adults in the UK, it was the disease that confined the late Professor Stephen Hawking to a wheelchair.

Frontotemporal dementia is a form of dementia that causes changes in personality and behaviour, and language difficulties.

Frontotemporal dementia causes changes in personality and behaviour and language problemsFrontotemporal dementia causes changes in personality and behaviour and language problems

A characteristic of both is the build-up of misfolded RNA-binding proteins, including a protein called FUS, in the brain and spinal cord. It leads to the death of neurons, preventing them communicating with each other and reaching muscles.

FUS proteins are able to change from small liquid droplets to jelly-like gels inside nerve cells. As they condense from droplets to gel, they capture RNA and transfer it to synapses, which make connections with other neurons. Here, the protein melts and releases the RNA – which are instructions for creating new proteins vital to keeping the synapses working properly, particularly during memory formation and learning.

In people with these diseases, the proteins get stuck as abnormally dense gels, trapping the RNA, leading to the damage of nerve cells by blocking their ability to make the proteins they need.

This ultimately causes the death of neurons in the brain and spinal cord.

The researchers found enzymes are responsible for enabling FUS to change form. But in frontotemporal dementia, gelling was caused by defects in the chemical modification of FUS. In motor neurone disease, it was caused by mutations in the FUS protein itself, meaning it was unable to change form.

Professor Peter St George-Hyslop, from the Cambridge Institute for Medical Research, 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.”

The potential therapeutic targets identified are the enzymes regulating the chemical modification of FUS and the molecular chaperones that enable FUS proteins to change form.

The study, reported in Cell, was funded by Wellcome.

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. Through their research, the team have uncovered promising new ways to tackle these diseases.”

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