Yak Gene Could Repair Damaged Nerves in Multiple Sclerosis

Every nerve fibre in your brain and spinal cord is wrapped in something a bit like electrical tape. The myelin sheath, as it’s called, is a fatty insulating layer produced by specialist cells called oligodendrocytes, and without it, nerve signals lose their speed and coherence. In multiple sclerosis, the immune system attacks this layer directly. In premature infants, oxygen deprivation during development can prevent it forming properly in the first place. Once damaged, it stubbornly refuses to regenerate. That failure of repair, more than the initial injury itself, is what drives the lasting disability in both conditions. And for decades, nobody could work out why the regeneration machinery so often stalls.

A team of researchers at Shanghai Jiao Tong University School of Medicine think part of the answer may have been living at altitude all along.

For several years, comparative genomic surveys have been picking up a recurring pattern in the DNA of animals native to the Tibetan Plateau. Yaks, Tibetan antelopes, and a handful of other plateau species all carry the same single amino acid change in a gene called Retsat: a substitution at position 247, where a glutamine has been replaced by an arginine. The plateau sits at an average elevation of roughly 14,700 feet, and chronic low oxygen is an unrelenting feature of life there. The assumption, when the mutation was first identified, was that it helped animals cope with that oxygen deficit somehow. How remained unclear. Retsat encodes an enzyme involved in processing vitamin A derivatives, and nobody had particularly thought to look at its effects on the brain’s white matter.

Liang Zhang’s team decided to look.

They introduced the Q247R mutation into mice and subjected newborn animals to ten percent oxygen (equivalent to living above 13,000 feet) for about a week. The effects were measurable and consistent. Mutant mice performed significantly better on tests of learning, memory, and social behaviour than standard animals exposed to the same conditions. When the researchers examined the brain tissue, they found the reason: the high-altitude gene mice had substantially more myelin surrounding their nerve fibres. The mutation was, somehow, protecting the insulating sheath that low oxygen would otherwise damage.

The question was how. What followed was several years of careful cell biology, tracing the pathway from gene to enzyme to molecule to therapeutic effect. The mutation, it turns out, increases the activity of the Retsat enzyme, which converts retinol (vitamin A) into a metabolite called ATDR. Neurons with the Q247R variant produce more ATDR, and then convert it further, via sequential oxidation, into a compound called ATDRA. This second molecule is the active signal. ATDRA passes from neurons to the nearby oligodendrocyte progenitor cells that are waiting, somewhat passively, to mature into myelin-producing oligodendrocytes. When ATDRA reaches them, it activates a receptor called RXR-gamma, which drives their differentiation. More mature oligodendrocytes; more myelin.

What makes this particularly striking is that the signalling is non-cell-autonomous. The mutation doesn’t act inside the myelin-producing cells themselves; it acts in neurons, which then send a paracrine signal across to the progenitor cells next door. Zhang and his colleagues found that conditioned medium from mutant neurons (but not from normal neurons) could drive OPC differentiation in a dish, and that this effect survived filtration to remove any large proteins. The active molecule was something small, and it was made in neurons, not in the oligodendrocyte lineage at all. There’s even evidence that the conversion machinery runs along neuronal processes rather than just in cell bodies, suggesting something close to a localised relay: neuron converts ATDR to ATDRA near the axon surface; ATDRA diffuses to adjacent progenitor cells; progenitors receive the signal and mature.

MS treatments today are, almost without exception, immunosuppressants. They slow the immune attack, sometimes quite effectively, but they don’t directly promote the repair that patients and clinicians actually need. Zhang’s team tested ATDR in a mouse model of MS-like autoimmune encephalomyelitis and found that it reduced clinical severity and improved motor function, accompanied by substantially better myelin preservation. “ATDR is something everyone already has in their body,” Zhang notes. “Our findings suggest that there may be an alternative approach that uses naturally occurring molecules to treat diseases related to myelin damage.”

ATDR has a practical advantage that designed drugs often lack: it crosses the blood-brain barrier efficiently. Once inside, neurons convert it to the active form. The molecule is, in effect, a prodrug that leverages cellular machinery already present in the brain to generate the signal where it’s needed. In the laboratory models tested, neither ATDR nor ATDRA caused weight loss or measurable cell death, which is a reasonable early sign of tolerability. The team also found that liver cells expressing the mutant gene could elevate ATDR and ATDRA levels in the brain via the bloodstream, hinting that the pathway might be engaged systemically as well as locally.

There are caveats worth sitting with. The work was done entirely in mice, and the gap between rodent models and human MS is well-documented and wide. The exact structural reason the Q247R mutation enhances enzyme activity remains unknown. Independent expert commentary on the findings hasn’t yet been widely gathered. And while the Q247R variant is associated with plateau-adapted animals, the precise evolutionary pressure that selected for it hasn’t been nailed down: whether it’s primarily oxygen-related, something else, or a combination, remains an open question.

Still, the conceptual move here is rather elegant. Rather than designing a new therapeutic molecule from scratch, Zhang’s team followed an evolutionary clue (a mutation that nature has been running in large mammals at altitude for a very long time) and traced it to a pathway that the human brain already uses, just perhaps not at full capacity. “Evolution is a great gift from nature,” Zhang says, “providing a rich diversity of genes that help organisms adapt to different environments. There is still so much to learn from naturally occurring genetic adaptations.”

The next step will be understanding what ATDRA does, mechanistically, once it binds RXR-gamma in progenitor cells; the full downstream transcriptional programme remains to be characterised. Longer-term pharmacokinetic studies in larger animals would also be needed before any clinical translation becomes credible. But the fundamental finding is: neurons can be induced to send a pro-myelination signal, by a molecule derived from vitamin A, and this signal can be boosted by a gene variant that plateau yaks have been carrying for millennia. Whether that signal can be reliably amplified in human patients with MS or neonatal white matter injury is the question that will define whether this research has a clinical future. The Tibetan Plateau, as an evolutionary laboratory, may have been working on the problem longer than we have.

DOI / Source: https://doi.org/10.1016/j.neuron.2026.01.013

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