The Yak Mutation That Could Help Repair the Brain (EP 56)

What can a yak living thousands of meters above sea level teach us about repairing the human brain?
In Episode 56 of From First Principles, Lester Nare and Krishna Choudhary break down a new Neuron paper that traces an evolutionary adaptation found in high-altitude animals to a previously hidden pathway involved in building and repairing myelin.
Summary
• What myelin actually does and why losing it disrupts neural communication
• How multiple sclerosis damages myelin and why the brain’s natural repair process eventually fails
• Why oligodendrocyte precursor cells can remain present in damaged tissue without successfully rebuilding myelin
• Why current therapies are better at slowing further damage than restoring what has already been lost
• The challenge of getting drugs across the blood-brain barrier while maintaining target specificity
• How evolutionary pharmacology has previously produced medicines from adaptations found in snakes and Gila monsters
• The RETSAT Q247R variant identified in animals adapted to the hypoxic environment of the Tibetan Plateau
• How researchers engineered the high-altitude variant into mice and tested its effect on myelin
• The surprising discovery that neurons — rather than the myelin-producing cells themselves — generate the key repair signal
• How RETSAT increases ATDR, which neurons convert into ATDRA
• How ATDRA activates RXR-γ in oligodendrocyte precursor cells and promotes their differentiation
• How administration of ATDR promoted remyelination across multiple preclinical models
• Why the result is scientifically promising but still far from a proven human treatment
Featured Paper
A gain-of-function Retsat variant from high-altitude adaptation promotes myelination via a neuronal dihydroretinoic acid-RXR-γ pathway
Neuron, 2026
DOI: 10.1016/j.neuron.2026.01.013

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