Scientists have identified a genetic mutation that helps protect the brain function of animals that live in high-altitude, low-oxygen environments. This mutation has provided new insights into how nerves could regenerate after experiencing damage to their protective insulation, known as the myelin sheath. These findings may help scientists find new ways to help people who have diseases like multiple sclerosis (MS), in which myelin is damaged by the immune system. The findings have been reported in Neuron.
Previous studies have shown that animals like yaks and Tibetan antelopes that live on the Tibetan plateau at an average elevation of 14,700 feet (4,480 meters) carry a change in a gene known as Restat. It’s been hypothesized that this mutation boosts normal brain function in these animals while they live under chronically low oxygen conditions.
"Evolution is a great gift from nature, providing a rich diversity of genes that help organisms adapt to different environments," noted corresponding study author Liang Zhang of Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. "There is still so much to learn from naturally occurring genetic adaptations."
Many nerve cells are surrounded by myelin, which helps neural signals move rapidly through the nervous system. But problems in myelin can arise and lead to serious problems. In MS, autoimmune dysfunction leads to the destruction of myelin. The myelin sheath can also experience damage during the normal course of aging, when blood flow to the brain begins to get lower; this can increase the risk of vascular dementia and other disorders. A lack of oxygen in development can also cause myelin damage and may lead to cerebral paralysis in newborns.
In this study, the researchers wanted to know if the Restat mutation seen in high-altitude animals was able to reduce or prevent myelin damage. They created a mouse model that carried the Restat mutation. These mice and those without the mutation were raised from birth in low-oxygen conditions to mimic those that occur around 13,000 feet (3,962 m) for about one week.
This effort showed that when mice reared in low oxygen carried the Restat mutation, their performances on a variety of behavioral and cognitive tests were better than mice reared in low oxygen that did not carry the Restat mutation.
When the researchers assessed the brains of these mice, those carrying the Restat mutation also had more myelin sheathing their neurons compared to those without the mutation.
Additional work showed that when mice carried the Retsat mutation, myelin sheath damage that is similar to what is seen in MS was repaired significantly faster and more comprehensively following an injury. Areas with myelin injuries also contained more cells called mature oligodendrocytes that generate myelin.
The Restate mutation could be boosting the activity of an enzyme that can produce various metabolites from vitamin A, such as one known as ATDR. Mice with the Restat mutation were found to be generating more of a vitamin A-derived metabolite called ATDR in their brains.
When ATDR was given to a mouse model of an MS-like disorder, symptoms decreased and motor function improved.
Right now, most MS treatments are aimed at reducing immune activity, said Zhang, and ATDR could present another therapeutic option. "ATDR is something everyone already has in their body. Our findings suggest that there may be an alternative approach that uses naturally occurring molecules to treat diseases related to myelin damage.”
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