Cells in MS lesions found to acquire mutations faster than healthy cells
Research shows potential connection tying inflammation to neuron death
Neurons, also called nerve cells, collected from brain lesions of people with multiple sclerosis (MS) were found to accumulate new genetic mutations at a significantly faster rate than healthy neurons did, according to a new report.
The researchers also found that neurons in such lesions exhibited distinct mutation signatures relative to cells outside lesions, suggesting there’s a distinct molecular process driving these mutations.
These findings could help shed new light on how inflammation — a core process implicated in MS — ultimately contributes to neurodegeneration and progressive disease. The scientists noted that future discoveries building upon these data could potentially identify novel treatments able to slow or stop MS progression.
“This research is significant because it’s the first to show that inflammation could be connected to the death of neurons in MS via accelerated mutation of the genetic code,” Trevor Kilpatrick, a professor at the University of Melbourne and director of The Florey Institute of Neuroscience and Mental Health in Australia, said in a university news story.
“Once we know for certain what molecular disruptions kill the neurons, we hope to find a way to save them, or keep them alive for longer to [minimize] progressive disease,” said Kilpatrick, also a study author and practicing neurologist. “It’s not a treatment for progressive MS yet, but it brings us closer to one.”
The study, “Neuronal somatic mutations are increased in multiple sclerosis lesions,” was published in the journal Nature Neuroscience by a team of researchers from institutions in Australia and China.
Investigating the mechanisms underlying disease progression in MS
In MS, the body’s own immune system wrongfully launches inflammatory attacks on healthy parts of the brain and spinal cord. This creates lesions — areas of damage from ongoing or past inflammation — that can be seen on MRI scans.
Both the accumulation and growth of these lesions have been found to contribute to disability progression and worsening symptoms in MS patients.
While neuroinflammation is known to be a key driver of neurodegeneration and disease progression in MS, the molecular mechanisms underlying this relationship remain not fully understood.
Somatic genetic mutations might play a role, according to MS research. While inherited mutations are passed down directly from parent to child via egg or sperm cells, somatic mutations are ones that arise in a person’s cells sometime after conception. They can happen at any time over the course of a person’s life, and may influence the health of the cells they affect.
In this work, the researchers set out to explore whether neuroinflammation might induce the formation of somatic mutations in nerve cells that contribute to disease progression.
Gene sequencing analyses were performed on nerve cells collected from post-mortem brain tissue of 10 MS patients — taken from chronic lesions and non-lesioned areas — as well as from five people without neurological disease, who served as a control group. Published data from an external control group of 11 people without neurological disease also were examined.
The results showed that cells from chronic MS lesions, which are linked with progressive disease, had, on average, more than 2,000 somatic mutations, compared with about 1,500 in non-lesioned MS cells or control cells.
Mutations accumulated 2.5 times faster in MS lesions vs. control cells
Statistical analyses ultimately estimated that mutations accumulated in MS lesions at a rate of 43.9 mutations per year — about 2.5 times faster than the rate of 17.7 mutations per year observed in non-lesioned MS cells and control cells.
In people with MS, the researchers suggest, healthy neurons and lesion neurons would have similar numbers of mutations probably until about age 35 or 40. Thereafter, however, the difference between them starts to emerge, with the mutation burden accelerating in lesion neurons, according to the investigators.
Justin Rubio, PhD, a study senior author and head of the neurogenetics group at The Florey, said “this means that by age 70, neurons in MS lesions have around 1,300 more mutations than normal neurons.”
Not only did we find there are more mutations in MS lesions, but they are also of different types to those seen in normal [aging], indicating a distinct molecular process causes mutations in MS.
Further analyses also identified distinct mutational signatures in the lesion neurons relative to normal cells. While some of these have been previously implicated as age-associated mutation patterns, others have been linked to DNA damage related to cancer and environmental toxins.
Allan Motyer, PhD, the study’s first author, who was involved in the work as a research fellow at the University of Melbourne, noted that these findings add to the data on MS lesions.
“Not only did we find there are more mutations in MS lesions, but they are also of different types to those seen in normal [aging], indicating a distinct molecular process causes mutations in MS,” Motyer said.
Altogether, the team wrote, “this research suggests that neuroinflammation is mutagenic [mutation-causing] in the MS brain, potentially contributing to disease progression.”
The scientists now are working to use these findings to explore new ways of treating progressive MS. The team thanked the families who donated brain tissue for the study, and also recognized MS Australia, which provided study funding.
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