Crucial link established between inflammation in MS and neuronal mutation
Australian scientists have for the first time opened the way for targeted and regenerative therapies that could prevent severe disease for multiple sclerosis patients
Australian scientists have for the first time demonstrated that inflammation in the brain in multiple sclerosis patients appears to drive an accelerated rate of mutations in crucial neurons, opening the way for targeted and regenerative therapies that could prevent severe disease.
The research by the Florey Institute and the University of Melbourne, published in the prestigious journal Nature Neuroscience, identifies how inflammation may contribute to MS progression, with neurons contained in lesions within the brains of people who suffer from MS accumulating mutations at a rate 2½ times neurons in the brains of people without the disease.
Mutations within neurons can disrupt a cell’s normal function or survival. Scientists are now working on trying to find out which molecular disruptions kill the neurons in MS patients, with the ultimate goal of disrupting those processes.
“This research is significant because it’s the first time that it essentially looks like we’ve found something that sort of sits between inflammation and what causes neurons to die in the brains of people with MS,” said the head of the Florey’s neurogenetics group, Associate Professor Justin Rubio, a neurogeneticist and lead author of the paper.
“So it is providing that sort of link between inflammation in the brain, the death of neurons and MS progression.”
Multiple sclerosis is a progressive neurological disease that affects 33,000 Australians and three million people worldwide.
The Florey research focused on somatic mutations, which are not inherited but occur over time in cells during ageing. The 10-year project studied brain tissues donated by families of people who passed away with MS.
The scientists compared mutations in neurons from the brains of 10 MS patients who had died with those from 16 people without MS.
They found that neurons in non-lesion areas and the brains of people without MS accumulated 17.7 mutations per year, while neurons in MS lesions accumulated 43.9 mutations per year.
“This means that by age 70, neurons in MS lesions have around 1300 more mutations than normal neurons,” Associate Professor Rubio said.
“We could be scratching the surface here. We’ve just looked at one type of mutation. We don’t know the full breadth of damage to DNA.
“What we think is going on is that the inflammation causes some sort of DNA damage to the neurons through various sorts of biochemical processes. What we have found is a new mechanism that wasn’t really known before, and we’re following this work up with MS Australia funding to try to take this information to help us basically find opportunities for new treatments.
“We’re hoping that this will sort of kick off a whole lot of other research around world on this particular mechanism, because that’s what you need if you want to develop a medicine for any condition. It really helps if you know what’s going on.”
Andrew Morrish, 63, was diagnosed with MS 24 years ago. A retired microbiologist, his condition has been well managed with medication and has not yet become progressive.
Dr Morrish is keenly watching developments as a result of the Florey research as it could provide the key to preventing MS developing into the progressive form of the disease, in which neurological symptoms get worse and commonly result in disability.
“To me, the key benefit of this fundamental research is it may lead to a therapy or a cure, which would be wonderful for everyone impacted by MS,” he said.
Co-author on the paper, Florey researcher and practising neurologist Professor Trevor Kilpatrick, said: “I think this research opens up Pandora’s box. This is a really, really significant finding. There’s a whole plethora of work required now to understand the implications and how to basically use this research to benefit patients.
“The question is, are there particular patterns of mutations in particular genes which are common between people with MS?
“This is showing us where the dark alley is and where the light now is being applied. And so it comes down to functional studies to understand hazards and the consequences of those mutations, and what happens to the nerve cells when those mutations are present and how to avert them.”
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