Gene on X chromosome may fuel higher MS risk for women: Study
When it was deleted in mouse model of disease, symptoms eased in females
A gene on the X chromosome that is more active in women than men appears to drive inflammation in the brain, helping to explain why women are more likely to develop neurological diseases such as multiple sclerosis (MS) and Alzheimer’s disease, according to a study out of the University of California, Los Angeles (UCLA).
“It has long been known that there are sex differences in the brain. These can impact both health and neurological diseases,” Rhonda Voskuhl, MD, director of the MS Program at UCLA Health and lead neurologist for the UCLA Comprehensive Menopause Program, said in a university press release. Voskuhl led the study.
When researchers deleted the KDM6A gene from microglia, the brain’s resident immune cells, in a mouse model of MS, symptoms of the disease eased significantly in females, but not in males.
“Our results suggest that KDM6A might contribute to sex differences in susceptibility to MS,” researchers wrote in “Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles,” which was published in Science Translational Medicine.
MS, Alzheimer’s disease each affect women more often than men
In MS, the immune system mistakenly attacks and damages healthy tissue in the brain and spinal cord. Women are about three times more likely to develop the disease than men, a difference thought to be driven mainly by sex-related hormones.
“Multiple sclerosis and Alzheimer’s disease each affect women more often than men, about two to three times as often. Also, two-thirds of healthy women have ‘brain fog’ during menopause. These new findings explain why and point to a new treatment to target this,” said Voskuhl, who is also a professor of neurology at UCLA Health.
In humans, sex is determined by chromosomes. Women typically have two X chromosomes, while men have one X and one Y. To keep things balanced, one of the X chromosomes in women is mostly “turned off” early in development so that the amount of X-linked genes is about the same in both sexes.
However, some genes on the X chromosome escape this silencing process and stay active on both copies. One of them is KDM6A, meaning women naturally make higher amounts of the KDM6A protein than men do.
The genes on the X chromosome tend to promote inflammation, which can be beneficial in fighting infections during childbearing years. In women, this effect is normally kept in check by estrogen, a hormone with anti-inflammatory and brain-protective properties.
“As women age, menopause causes loss of estrogen, unleashing the proinflammatory and neurodegenerative effects of this X chromosome [on] the brain immune cell,” Voskuhl said.
Blocking gene with diabetes medication eased symptoms in female mice
In this study, Voskuhl’s team explored whether higher KDM6A activation influenced the activity of microglia, immune cells in the brain known to play a key role in many neurological conditions.
The researchers deleted the gene specifically from those cells in a mouse model of MS, and results showed that females had less severe symptoms and lower markers of active inflammation. Deleting the gene in microglia from female mice also reversed other changes in the spinal cord linked to the disease. In males, however, this had only minimal effects.
Consistent with these effects, blocking KDM6A with metformin, a diabetes medication, also eased symptoms of MS in female mice, but not in males.
Studies of human microglia confirmed that KDM6A is produced at higher levels and that more genes are dysregulated in women with MS than in men. These findings suggest that KDM6A plays a key role in the sex differences seen in MS and could be a target for treatments designed specifically for women.
“This is consistent with there being ‘more to block’ in females due to having two copies of the X-linked gene,” Voskuhl said. “This has implications for the clinic. Women may respond differently to metformin treatment than men.”
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