A brain repair kit that helps yaks and other animals naturally cope with low oxygen levels at high altitudes may point to a new way to treat brain diseases such as multiple sclerosis. In mice with brain damage that mimics MS, the kit’s tools lessened signs of damage in young mice exposed to low oxygen and improved symptoms of MS in adult mice, researchers report March 13 in Neuron.
Previous research found that animals living on the Tibetan Plateau, such as yaks and antelopes, carry a mutation in a gene called Retsat. Their lowland counterparts lack the mutation, leading scientists to suspect that it helps protect the brain in low-oxygen environments.
“People usually think it’s because of better lung capability, but I wondered whether evolutionary adaptation changes the brain,” says Liang Zhang, a neuroscientist at Shanghai Jiao Tong University. In particular, he was intrigued that these animals have normal white matter in their brains.
White matter makes up about half the brain; it consists of bundles of nerve fibers that allow different brain regions to communicate. This neural wiring is wrapped in myelin, a fatty substance that ensures nerve fibers conduct signals efficiently. In MS, the immune system attacks myelin, leading to neurological symptoms and problems with balance and coordination.
Myelin production requires a lot of energy, which the brain gets from oxygen. Low oxygen levels, known as hypoxia, can therefore disrupt myelination. During gestation, such disruption can lead to conditions such as cerebral palsy in newborns.
To tease out if Retsat plays a role in protecting brain health, Zhang and colleagues put young mice in a low-oxygen environment comparable to the thin air at 5,800 meters for a week. Mice engineered to have the genetic mutation performed better than normal mice in tests of learning, memory and social behavior, and had more myelin in their brains.
In a separate test, adult mice with the mutation regenerated myelin better than mice without it and had more mature oligodendrocytes, the brain cells that produce myelin. Experiments revealed that the Retsat gene helps neurons convert a vitamin A–related molecule called ATDR into a form called ATDRA, which triggers the creation of mature oligodendrocytes.
When young mice exposed to low oxygen received injections of ATDR and ATDRA, both molecules reduced hypoxia’s impact on myelin in the brain. Giving ATDR to adult mice with MS-like brain damage significantly improved their symptoms.
“It’s beautiful science, but there’s a big step before this gets to humans,” says Anna Williams, a neurologist at the University of Edinburgh, who was not involved in the study.
Current MS treatments aim to slow disease progression, mainly by suppressing the immune system. Finding ways to repair existing nerve damage has proven more elusive. Researchers are working on ways to regenerate myelin, and one drug is in early clinical trials. But an earlier drug that increases levels of mature oligodendrocytes using the same molecular switch as ATDRA caused serious side effects, so researchers stopped pursuing this avenue.
Whether molecules already found in the body will fare better is unclear. “It’s maybe safer than [a drug], but we don’t know what concentration is needed for repair,” Zhang says. “ATDR has many functions, so we should be careful of side effects.”
If the approach proves safe, it could help treat conditions involving myelin damage, including all neurodegenerative diseases — even stroke. The finding shows the power of looking to nature for clues about how evolution solves challenges, Zhang says. “We can discover a lot of secrets from evolutionary adaptations that we can use for medical conditions.”
