A Gene Found in Yaks Offers Hope for Treating Multiple Sclerosis and Other Brain Diseases

Researchers have identified a genetic adaptation in yaks – and other animals that thrive at high altitudes – that may hold a key to repairing nerve damage caused by conditions like multiple sclerosis (MS). A study published March 13 in Neuron suggests that a specific gene, Retsat, helps protect the brain from the damaging effects of low oxygen, and that harnessing this natural defense mechanism could lead to new therapies.

Multiple sclerosis is a chronic, often debilitating disease that affects the central nervous system – the brain and spinal cord. It occurs when the immune system attacks myelin, the protective sheath around nerve fibers. This damage disrupts communication between the brain and the rest of the body, leading to a range of symptoms including muscle weakness, fatigue, and difficulty with coordination and balance. Mayo Clinic provides a comprehensive overview of MS symptoms and causes.

The High-Altitude Advantage

The research began with an observation: animals like yaks and Tibetan antelopes, native to the oxygen-thin air of the Tibetan Plateau, seem to be naturally protected from the neurological consequences of hypoxia (low oxygen levels). Scientists suspected a genetic basis for this resilience. Previous research had pinpointed a mutation in the Retsat gene as a potential factor. Animals without this mutation, when exposed to low oxygen, experience more significant neurological effects.

“People usually think it’s because of better lung capability, but I wondered whether evolutionary adaptation changes the brain,” explains Liang Zhang, a neuroscientist at Shanghai Jiao Tong University and lead author of the study. “In particular, I was intrigued that these animals have normal white matter in their brains.” White matter comprises roughly half of the brain’s volume and is crucial for efficient communication between different brain regions. Damage to white matter is a hallmark of MS and other neurological disorders.

How Retsat Protects the Brain

Myelin, the fatty substance that insulates nerve fibers, is essential for rapid and reliable nerve signal transmission. Producing myelin requires a substantial amount of energy, which is ultimately derived from oxygen. When oxygen levels drop, myelin production slows down or stops, leaving nerve fibers vulnerable. This disruption can have particularly severe consequences during development, potentially leading to conditions like cerebral palsy.

To investigate Retsat’s role, Zhang and his team exposed young mice to a low-oxygen environment mimicking the conditions at an altitude of 5,800 meters (approximately 19,000 feet) for one week. Mice genetically engineered to carry the yak-specific Retsat mutation fared significantly better than their unmodified counterparts. They exhibited improved performance in tests assessing learning, memory, and social behavior, and showed greater preservation of myelin in their brains.

Further experiments with adult mice revealed that the Retsat mutation also enhanced myelin regeneration in mice with brain damage resembling MS. The researchers discovered that the Retsat gene facilitates the conversion of a vitamin A-related molecule, ATDR, into another form called ATDRA. ATDRA, in turn, stimulates the production of mature oligodendrocytes – the brain cells responsible for creating and maintaining myelin.

Remarkably, directly administering ATDR and ATDRA to young mice exposed to low oxygen reduced the negative impact on myelin. Similarly, administering ATDR to adult mice with MS-like brain damage led to noticeable improvements in their symptoms.

From Yak Genes to Human Therapies: A Cautious Path Forward

While these findings are promising, experts caution that translating them into effective treatments for humans will require significant further research. “It’s gorgeous 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. The Mountain Press highlights this need for further investigation.

Current MS treatments primarily focus on slowing disease progression by suppressing the immune system. Repairing existing nerve damage has proven far more challenging. While some therapies aimed at promoting myelin regeneration are in early clinical trials, previous attempts to boost oligodendrocyte levels using a similar molecular pathway as ATDRA were halted due to serious side effects.

The researchers emphasize the potential advantages of utilizing naturally occurring molecules like ATDR, which are already present in the body. However, they acknowledge the need for careful evaluation of dosage and potential side effects. “ATDR has many functions, so we should be careful of side effects,” Zhang notes.

Beyond MS: Implications for Other Neurological Conditions

If the approach proves safe and effective, it could potentially benefit a wide range of conditions involving myelin damage, including stroke and other neurodegenerative diseases. The study underscores the value of studying evolutionary adaptations to uncover novel therapeutic strategies. “One can discover a lot of secrets from evolutionary adaptations that we can leverage for medical conditions,” Zhang concludes.

The next steps involve further preclinical studies to optimize the delivery and dosage of ATDR and ATDRA, as well as rigorous safety testing. Clinical trials will be necessary to determine whether this promising approach can translate into a meaningful treatment for people living with MS and other debilitating neurological disorders. Ongoing research will also focus on understanding the precise mechanisms by which Retsat protects the brain, potentially revealing additional therapeutic targets.