High-altitude survival gene may help reverse nerve damage

(Press-News.org) A genetic mutation that helps animals like yaks and Tibetan antelopes survive at high altitudes may hold the key to repairing nerve damage in conditions such as cerebral paralysis and multiple sclerosis (MS). The finding, publishing March 13 in the Cell Press journal Neuron, reveals a naturally existing pathway that promotes regeneration after nerve damage and could open new doors for treating diseases like MS by leveraging molecules that are already present in the human body. 

“Evolution is a great gift from nature, providing a rich diversity of genes that help organisms adapt to different environments,” says corresponding 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.” 

The myelin sheath is a protective layer that surrounds nerve fibers in the brain and spinal cord, allowing nerve signals to transmit efficiently. Insufficient oxygen during brain development can damage this layer, leading to conditions like cerebral paralysis in newborns. 

In adults, injuries to the myelin sheath are tied to MS, an autoimmune disease in which the immune system mistakenly attacks and destroys the myelin sheath. Reduced blood flow to the brain, often associated with aging, can also damage myelin, contributing to conditions such as cerebral small vessel disease and vascular dementia. 

In previous studies, researchers have found that animals living on the Tibetan Plateau—which has an average elevation of 14,700 feet—carry a mutation on a gene called Retsat. Scientists suspected that this mutation helps animals like yaks and Tibetan antelopes maintain healthy brain function despite chronically low oxygen levels.  

Zhang and his team set off to investigate if this mutation could prevent myelin sheath damage. They exposed newborn mice to low-oxygen conditions equivalent to elevations above 13,000 feet for about a week. Mice carrying the Retsat mutation performed significantly better in learning, memory, and social behavior tests than those with the standard version of the gene. Brain analyses also revealed that the high-altitude gene mice had higher levels of myelin surrounding their nerve fibers.  

The researchers then examined whether the Retsat mutation could repair myelin sheath damage similar to that seen in MS. They found that in mice carrying the mutation, the myelin sheath regenerated much faster and more completely after injury. The injury sites also had more mature oligodendrocytes, a type of cell responsible for producing myelin. 

Further investigation showed that mice with the mutation produced higher levels of ATDR, a metabolite derived from vitamin A, in their brains. The Retsat mutation appeared to increase the enzymatic activity that converts vitamin A into its metabolites, which in turn promotes the production and maturation of myelin-producing oligodendrocytes. When the team gave ATDR to mice with an MS-like disease, their disease severity decreased, and they showed improved motor function. 

Current treatments for MS mainly focus on suppressing immune activity, notes Zhang. “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,” he says.  

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This work was supported by the National Science and Technology Major Project, the National Natural Science Foundation of China, the China Postdoctoral Science Foundation, Shanghai Post-doctoral Excellence Program, the Natural Science Foundation of Shanghai, the 2024 Tibet Autonomous Region Science and Technology Plan Key R&D and Transformation Project, the Open Research Fund of Navy Medical University Basic Medical College, Yunnan Revitalization Talent Support Program Science & Technology Champion Project and the Yunnan Revitalization Talent Support Program. 

Neuron, Li et al., “A gain-of-function Retsat variant from high-altitude adaptation promotes myelination via a neuronal dihydroretinoic acid-RXR-γ pathway” https://www.cell.com/neuron/fulltext/S0896-6273(26)00013-9

Neuron (@NeuroCellPress), published by Cell Press, is a bimonthly journal that has established itself as one of the most influential and relied upon journals in the field of neuroscience and one of the premier intellectual forums of the neuroscience community. It publishes interdisciplinary articles that integrate biophysical, cellular, developmental, and molecular approaches with a systems approach to sensory, motor, and higher-order cognitive functions. Visit: http://www.cell.com/neuron. To receive Cell Press media alerts, contact press@cell.com. 

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