Summary: New research shows that female mice expressing only one maternal X chromosome experience more rapid brain aging and cognitive decline than those expressing both maternal and paternal X chromosomes.
Maternal X accelerates aging of the hippocampus, a key region for memory and learning, and silences certain genes essential for brain health. Using CRISPR, researchers reactivated these suppressed genes, improving memory in older mice.
These results suggest that parental origin of the X chromosome influences brain aging and could explain individual differences in cognitive decline and susceptibility to brain diseases. Researchers hope this information will inform strategies to slow brain aging and address gender differences in diseases like Alzheimer’s.
Key facts:
- Link on brain aging: A maternal X chromosome accelerates aging and impairs memory.
- Impact of gene silencing: Some genes in the maternal X are silenced but not in the paternal X.
- Therapeutic potential: Reactivation of silenced genes improved memory in aging female mice.
Source: UCSF
Women are born with two X chromosomes and inherit one from each parent. But in each cell of their body, only one X chromosome is needed – so the other is randomly inactivated. Some cells use only a maternal X chromosome; others rely solely on the paternal X.
Now, researchers at UC San Francisco have discovered that when the brain cells of female mice express only one maternal X chromosome, their memory and cognitive abilities deteriorate more quickly than those of female mice that express both maternal and paternal X chromosomes.
The discovery, which appears on January 22 in Naturecould explain the variation in brain aging between the sexes, since men only inherit a maternal X, as well as the variation between women.
“These findings raise the possibility that some women who express more of their mother’s X chromosome by pure chance might have more cognitive impairment with aging or an increased risk of diseases like Alzheimer’s disease,” said Dena Dubal, MD. , PhD, professor of neurology. and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Diseases at UCSF, and the lead author of the new paper.
“Ultimately, this could also help us find constructive strategies to slow brain aging in both sexes. »
X marks the brain
Previous research has suggested that the X chromosome – of which most women have two and most men have only one – is essential for brain health. Mutations of the X chromosome often result in intellectual disability, and women born with only one X chromosome (a diagnosis known as Turner syndrome) may have cognitive impairments.
According to some researchers, the X chromosomes could help explain gender differences in cognition, verbal memory or risk of brain disease.
“Since the and first author. of the new work.
Dubal and Abdulai-Saiku were particularly interested in whether the origin of the X chromosome – from mom or dad – mattered to cells. They knew that when eggs and sperm form, chemical tags are added to certain genes on the chromosomes.
These marks differ depending on whether the chromosome comes from the mother (egg) or the father (sperm). The marks impact which genes are activated when each chromosome is used in cells.
In the new study, the research team bred female mice to either express only maternal X chromosomes or a mixture of maternal and paternal X chromosomes.
“X chromosome bias is common in humans, and there are certainly women walking around with much higher or lower levels of maternal X chromosomes than others, just by chance,” Dubal said.
“There has been little research into the potential consequences of this. »
The effect of maternal chromosomes
Dubal and Abdulai-Saiku found that female mice with only one active maternal X chromosome had poorer memory and learning abilities as they aged. In the brains of these mice, the maternal X chromosome accelerated the biological aging of the hippocampus – a brain area crucial for learning and memory.
“What we showed was that the brains of these animals really aged faster than those of their genetically identical sisters whose mom and dad X chromosomes were activated,” Dubal explained.
By carrying out detailed analyzes of the brain cells, the team was then able to identify certain genes that were completely inhibited on the maternal X chromosomes but not on the paternal ones.
When researchers used CRISPR gene-editing technology to activate inhibited genes on maternal X chromosomes in female mice, they became more intelligent at older ages.
“Together, all of these experiments suggest to us that the parental origin of an X chromosome can have an important 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 silenced genes on the maternal chromosome could provide an advantage earlier in life.
“It may be that this pattern of gene expression is actually very beneficial for brain development, but then there is this trade-off later in life,” she said.
Dubal hopes to continue studying the role of the X chromosome in brain aging and determine whether it can explain the risk of brain diseases or memory loss.
“The X chromosome you inherited from your mother turns off genes, accelerates aging and impairs cognition,” she said. “Can we reverse this trend? »
Authors: Other authors of the paper were Shweta Gupta, Dan Wang, Francesca Marino, Arturo J. Moreno and Barbara Panning of UCSF and Yu Huang and Deepak Srivastava of UCSF and the Gladstone Institutes.
Funding: Primary funding for the study was provided by the National Institute of Aging (RF1AG079176, RF1AG068325), the American Federation for Aging Research, the Bakar Aging Research Institute, and the Simons Foundation (1018027, 811225SPI).
Disclosures: Dena Dubal serves on the board of directors of the Glenn Medical Foundation, has consulted for Unity Biotechnology (unrelated to manuscript content) and SV Health Investors (unrelated to manuscript content), and is an associate editor at JAMA Neurology . All other authors declare no competing interests.
About this research news on genetics and brain aging
Author: Laura Kurtzman
Source: UCSF
Contact:Laura Kurtzman – UCSF
Picture:Image is credited to Neuroscience News
Original research:Free access.
“Maternal X chromosome affects cognition and brain aging in female mice” by Dena Dubal et al. Nature
Abstract
Maternal X chromosome affects cognition and brain aging in female mice
Female mammalian cells have two X chromosomes, one of maternal origin and one of paternal origin. During development, an X chromosome becomes randomly inactivated.
This makes either the maternalm) chromosome or the paternal X (Xp) inactive chromosome, causing X mosaicism which varies among female individuals, with some showing considerable or complete asymmetry of the X chromosome which remains active.
Parent-of-X origin can modify epigenetics via DNA methylation and possibly gene expression; thus, mosaicism could buffer dysregulated processes linked to aging and disease. However, whether X asymmetry or mosaicism alters functions in female individuals is largely unknown.
Here we tested whether tilting toward an activem the chromosome influences the brain and body, then demarcates the unique characteristics ofm neurons andp neurons. An activem chromosomes impair cognition in female mice throughout life and lead to worsening cognition with age.
Cognitive deficits were accompanied bym-mediated acceleration of biological or epigenetic aging of the hippocampus, a key center of learning and memory, in female mice.
Several genes have been imprinted on them chromosome of hippocampal neurons, suggesting silent cognitive loci. CRISPR-mediated activation of XmImprinted genes improved cognition in aging female mice.
So, them chromosome-impaired cognition, accelerated brain aging, and silenced genes that contribute to cognition in aging.
Understand howm impairs brain function could lead to a better understanding of the heterogeneity of cognitive health in women and the X chromosome-derived pathways that protect against cognitive deficits and brain aging.
