Mom’s X chromosome could speed up brain aging, study suggests microbiologystudy

Women are born with two X chromosomes and inherit one from each parent. But in every cell of their body, just one X chromosome is needed—so the other is randomly inactivated. Some cells use only a maternal X chromosome; others rely only on the paternal X.

Now, UC San Francisco researchers have found that when the brain cells of female mice express only a maternal X chromosome, their memory and cognitive skills deteriorate faster than female mice that express both maternal and paternal X chromosomes.

The discovery, which appears Jan. 22 in Nature, could explain the variation in brain aging between the sexes, since males inherit only a maternal X, as well as the variation between individual women.

“These findings raise the possibility that some women who express more of their mom’s X chromosome just by pure chance may have more cognitive impairment with aging or an increased risk for diseases like Alzheimer’s,” said Dena Dubal, MD, Ph.D., a professor of neurology and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease at UCSF, and the senior author of the new paper.

“Ultimately, it could also help us find constructive strategies for slowing brain aging in both sexes.”

X marks the brain

Previous research has hinted that the X chromosome—of which most women have two and most men have just one—is vital to brain health.

Mutations in the X chromosome often cause intellectual disability, and women born with just one X chromosome (a diagnosis known as Turner Syndrome), can have cognitive impairments. X chromosomes, some researchers hypothesize, could help explain sex differences in cognition, verbal memory, or brain disease risk.

“Given the fact that the X chromosome is enriched for brain-related genes, it became very important for us to know what roles it might be playing in brain aging,” said Samira Abdulai-Saiku, Ph.D., a UCSF postdoctoral fellow and first author of the new work.

Dubal and Abdulai-Saiku were especially interested in whether the origin of the X chromosome—from mom or from dad—mattered to cells. They knew that when egg and sperm cells form, chemical tags are added to certain genes on the chromosomes.

These marks differ depending on whether the chromosome is from the mother (egg) or father (sperm). The marks impact what genes are activated when each chromosome is used in cells.

In the new study, the research team bred female mice either to express only maternal X chromosomes, or a mixture of maternal and paternal X chromosomes.

“Skewing of the X chromosome is common among humans, and there are certainly women who are walking around with much higher or lower levels of maternal X chromosomes than others, just by chance,” said Dubal. “There has been little research on the potential consequences of this.”

The effect of maternal chromosomes

Female mice with only an active maternal X chromosome, Dubal and Abdulai-Saiku discovered, showed poorer memory and learning abilities as they aged. In the brains of these mice, the maternal X chromosome sped up biological aging in the hippocampus—a brain area crucial for learning and memory.

“What we showed is that these animals’ brains were really aging faster than the brains of their genetically identical sisters who had both mom’s and dad’s X chromosomes turned on,” explained Dubal.

Carrying out detailed analyses of the brain cells, the team was then able to identify certain genes that were completely silenced on maternal X chromosomes but not paternal ones.

When the researchers used CRISPR gene editing technology to activate the silenced genes on maternal X chromosomes in female mice, they became smarter in their old age.

“Together, all these experiments suggested to us that the parental origin of an X chromosome can have a big impact on brain health,” Abdulai-Saiku said.

Evolutionary roots?

The new study was not designed to test exactly why the maternal X chromosome would accelerate brain aging compared to the paternal X chromosome. However, Dubal hypothesized that the genes silenced on the maternal chromosome could convey an advantage earlier in life.

“It may be that this gene expression pattern is actually really beneficial to brain development, but then there is this tradeoff later in life,” she said.

Dubal hopes to continue studying the role of the X chromosome in brain aging, and whether it can explain people’s risk of brain diseases or memory loss.

“The X chromosome you inherited from your mom is turning off genes, accelerating aging, and impairing cognition,” she said. “Can we reverse this?”