Yaks and other animals have adaptations that allow them to naturally cope with low oxygen levels at high altitudes. New research indicates these mechanisms may help develop new treatments for brain diseases such as multiple sclerosis. In mice with brain damage, the adaptations lessened the signs of damage in young mice exposed to low oxygen and improved the symptoms of MS in adult mice, the researchers reported in Neuron this week.
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Previous research found that yaks and other animals on the Tibetan Plateau have a mutation in a gene called Retsat that does not appear in animals living at lower altitudes. The mutation could help protect the brain in low-oxygen environments.
In MS, the immune system attacks myelin, a fatty substance that allows nerves to conduct signals efficiently. This leads to neurological symptoms and issues with balance and coordination. Similarly, low oxygen levels can disrupt the production of myelin, which requires a lot of energy.
Testing the yak’s genetic “turbocharge” in mice
To determine if the mutation does protect the brain, the researchers put mice in a low-oxygen environment for one week. Mice with the engineered mutation performed better than normal mice in learning, memory and social tests and also had more myelin in their brains.
In another test, adult mice with the mutation regenerated myelin better than those without it and had more mature oligodendrocytes, which are the cells that produce myelin. Further experiments revealed that the Retsat gene helps neurons convert ATDR, a molecule related to vitamin A, into ATDRA, which triggers the creation of mature oligodendrocytes.
When young mice in low oxygen received injections of ATDR and ATDRA, both molecules reduced the impact of low oxygen on myelin. Adult mice with brain damage who received ATDR had improved symptoms.
From mountain peaks to medical breakthroughs
There’s still a long way to go before any innovations inspired by this finding start to make their way to patients. Currently, treatments for MS suppress the immune system to slow disease progression. One drug that increased levels of mature oligodendrocytes by targeting the same RXR-𝛾 receptor as ATDRA was abandoned after it caused serious side effects.
Still, this finding could help treat conditions involving myelin damage. It offers a blueprint for remyelination, a possible way to restore lost function rather than just slowing down decline. A drug based on ATDR and ATDRA, metabolites that already exist in the body, could flip the repair switch in the brain and trigger remyelination without the side effects that targeting the receptor caused.
Beyond MS, this mechanism could have implications for treating traumatic brain injuries or even age-related white matter loss. However, experts caution that this isn’t as simple as taking Vitamin A supplements; the challenge lies in mimicking the yak’s unique genetic “turbocharge” to ensure the molecules reach the brain and perform their repair work effectively.
