Multiple sclerosis is an autoimmune and neurological disorder that strikes women about three times as often as men. There are many suspected causes of MS, including environmental factors (that may be related to geography), genetic influences, or certain infectious illnesses like Epstein-Barr virus (EBV). Alzheimer’s disease, which has been linked to neuroinflammation, also strikes women more frequently than men.
Researchers have now identified a gene called Kdm6a that is located on the X chromosome that could help explain why certain diseases with an inflammatory, neurological basis arise in women far more often than in men. The findings have been reported in Science Translational Medicine.
In this study, the investigators analyzed a mouse model of MS, and focused on female mice. They found that Kdm6a was not subject to X-inactivation. Usually, when a gene is located on the X chromosome, one copy of that gene is inactivated by the cells in individuals who carry two X chromsomes because otherwise, two copies of that gene would be expressed. If an X-linked gene is not inactivated, high levels of this gene are expressed. When Kdm6a was deactivated in female mice modeling MS, the symptoms of their disease were relieved. This gene could be driving high levels of inflammation in females, and increasing the risk of diseases like Alzheimer's disease and multiple sclerosis.
"It has long been known that there are sex differences in the brain. These can impact both health and neurological diseases," said lead study author Dr. Rhonda Voskuhl, director of the Multiple Sclerosis Program at UCLA Health and lead neurologist for the UCLA Comprehensive Menopause Program. "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."
The researchers also reduced the expression of Kdm6a with a drug known as metformin, which is a common diabetes treatment. This had the same effect, and lowered levels of neuroinflammation.
When these approaches were applied to male mice, there were no changes. "This is consistent with there being 'more to block' in females due to having two copies of the X-linked gene," said Voskuhl, who is also a professor of neurology at UCLA Health.
"It's also why females are more likely to get MS and [Alzheimer's] than males. This has implications for the clinic. Women may respond differently to metformin treatment than men."
Sources: University of California, Los Angeles (UCLA), Science Translational Medicine
