Myelin repair mechanism found in animal genetics, says scientist

A team of scientists in China, attempting to understand the function of a genetic mutation commonly found in animals living at high altitudes, discovered a previously unknown mechanism key to myelin repair.

The discovery could have important implications for diseases such as multiple sclerosis (MS), which is marked by inflammation that damages myelin – a fatty substance that wraps around nerve fibres – in the brain and spinal cord. In MS, myelin damage disrupts neural signalling, leading to MS symptoms.

The scientists were studying a mutation in the Retsat gene, which helps animals adapt to low oxygen levels, and found that it promotes myelin repair.

In mouse experiments, the team showed that low oxygen levels suppress myelin formation, but animals engineered to carry the Retsat mutation were able to produce more myelin when reared in a low-oxygen environment.

‘Evolution is a great gift from nature, providing a rich diversity of genes that help organisms adapt to different environments,’ Liang Zhang, PhD, co-author of the study at Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, said in a journal news story. ‘There is still so much to learn from naturally occurring genetic adaptations.’

Disease-modifying treatments for MS reduce disease activity and slow disease progression by dampening inflammation, but none has been proven to facilitate remyelination (myelin repair), which could theoretically help reverse the disease and restore lost functions. Scientists worldwide are working to find ways to promote remyelination.

Long-term exposure to low oxygen levels is known to disrupt myelin formation and repair and lead to severe neurological issues, but animals living in high altitudes appear to have developed a range of adaptations that help them maintain myelin integrity.

The researchers set out to understand whether a known adaptation, a mutation in the Retstat gene called Q247R, is involved in these animals’ ability to produce and repair myelin under low-oxygen conditions. They engineered mice carrying the mutation, then raised them in environments similar to what’s found at high altitudes.

The mouse study showed that the mutation did not appear to affect the growth of red blood cells, which carry oxygen through the body and are often important for managing low oxygen.

Analyses of metabolism and energy consumption – also processes that are highly dependent on oxygen – showed no notable difference in mice carrying the Retsat Q247R mutation.

What these mice did show was distinct differences in the amount of myelin in their brains. At low oxygen levels, mice without the mutation don’t produce as much myelin as normal in early development, leading to severe demyelination. But mice with the Retsat Q247R mutation produced a normal amount of myelin even under low-oxygen conditions.

Myelin in the brain and spinal cord is produced primarily by specialized cells called oligodendrocytes. The researchers found that the Retsat Q247R mutation accelerated oligodendrocyte maturation in early development.

Further tests in adult mice showed that the Retsat Q247R mutation also led to faster, more efficient remyelination after the mice were treated with myelin-damaging chemicals. Again, this was accompanied by increased oligodendrocyte growth.

‘Collectively, these data demonstrate that the Retsat Q247R mutation enhances oligodendrocyte differentiation, leading to improved developmental myelination under [low-oxygen] stress and conferring an accelerated remyelination in the adult brain following demyelinating injuries,’ the researchers wrote.

Based on their findings, the scientists suspected that the Retsat Q247R mutation might directly promote oligodendrocyte growth. But additional tests showed that this wasn’t the case. Instead, the researchers found that the Q247R mutation makes the Retsat enzyme more active in nerve cells.

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