A gene related to the X chromosome, referred to as KDM6A, exhibits heightened function in females contrasted with males and is associated with cerebral inflammation, potentially illuminating the elevated prevalence of multiple sclerosis identified in females.(Image credit: quantic69/Getty Images)
A fresh investigation in mice implies that brain irritation may be stimulated by a gene situated on the X chromosome.
Additionally, in female mice, who possess two X chromosomes, a medication for diabetes identified as metformin could function to neutralize that inflammation.
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A Contrast Between Genders
Our systems are guarded by immune cells that offer safeguard against microbes and viruses, but at times, these protections become harmful to us. Within the autoimmune illness multiple sclerosis (MS), as an example, the immune system assaults myelin, the greasy protection encircling the nerve fibers present in the brain and spinal column. This gives rise to manifestations for example, muscle frailty and trouble in ambulating, as well as issues pertaining to recall and contemplation.
The ailment occurs two to three instances more routinely in females compared to males, and symptoms frequently intensify post-menopause. Nevertheless, up until recently, scientists were unsure as to the reason.
Dr. Rhonda Voskuhl, a neurologist and neuroscientist situated at UCLA, has been delving into that riddle for decades. Clinical configurations displaying amplified ailment frequencies in females constitute “an exceptionally valuable clue” that the disparity could be impelled by a gene associated with the X chromosome, Voskuhl informed Live Science.
That stems from the fact that females typically inherit an X chromosome originating from each parent, whereas males solely inherit one originating from their mothers. Typically, one collection of X-linked genes in females is hushed, leaving just one active gene stemming either from the mother or from the father. Nevertheless, a selection of genes evade this “X inactivation,” Voskuhl informed Live Science, bestowing females an augmented dosage of X-linked gene function.
To ascertain whether X-linked genes might elucidate females’ amplified frequencies of MS, Voskuhl and her associates scrutinized current information pertaining to human microglia, the principal immune cells within the brain. They examined cells originating from both males and females diagnosed with MS.
In contrast with those originating from males, the microglia of females displayed amplified concentrations of a protein designated KDM6A, which is encrypted by the KDM6A gene situated on the X chromosome. The cells of females additionally manifested elevated concentrations of immune-relevant gene function.
To probe into the function of the KDM6A gene within the brain, Voskuhl and associates employed strategies to “eliminate” the function of the gene in laboratory mice — explicitly within the microglia of the rodents. Subsequently, they induced a condition resembling MS within the mice employing established methodologies.
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Female knockout mice showed enhanced gait, and their cerebral tissue exhibited diminished nerve impairment along with amplified intact, myelin-protected nerve fibers contrasted with female mice possessing a functional KDM6A gene. Knockout female mice additionally manifested diminished infiltration by immune cells, referred to as T cells, contrasted with female mice bearing functioning KDM6A genes.
However, erasing the KDM6A gene exerted no influence within male mice, the researchers stated in the fresh investigation, issued Oct. 15 within the journal Science Translational Medicine. The discovery implies that the KDM6A gene might stimulate cerebral inflammation in females due to the fact that they possess two copies of it, and one copy “evades” silencing. Consequently, females might acquire an escalated dosage of the KDM6A protein.
The researchers subsequently searched for a medication that could replicate the impacts of erasing KDM6A. Prior investigations had illustrated that metformin has the capacity to impede the KDM6A enzyme within other cell variants, therefore Voskuhl speculated whether it might exert an identical influence in microglia. Her team discovered that metformin alleviated cerebral inflammation and ameliorated manifestations in female mice while exerting minimal influence in male mice.
This alludes to the capability for treatments specific to gender, considering that both the KDM6A function and the impacts of metformin diverge among males and females. If such a treatment were solely assessed in males or in a mixed collection of study participants, its potency in females might remain unnoticeable, Voskuhl elucidated; consequently, information originating from females would necessitate gathering and assessing independently.
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“It constitutes a brilliant investigation,” stated Dr. Lawrence Steinman, a neurologist at Stanford University who remained uninvolved within the fresh endeavor, given that it pinpoints one of the pivotal genes rendering females more susceptible to MS. It embodies “an additional stride forward” in comprehending the manner in which KDM6A shapes immune function within the brain and sustains microglia “on the tranquil facet,” Steinman communicated to Live Science.
Follow-up investigations and clinical examinations remain requisite to pinpoint the most clinically efficacious approaches to impede KDM6A within the microglia of females, and to affirm that such a medication would prove therapeutically advantageous.
These discoveries additionally allude to an interplay amid hormones and chromosome-associated inflammation. Prior endeavors have illustrated that estrogen generally counteracts the inflammation within the system, assisting in equilibrating immune function that defends the female brain against pathogens and surplus inflammation during the reproductive span, Voskuhl conveyed.
“Therefore, when estrogen concentrations decline during menopause,” she articulated, “you forfeit that safeguard.”
Disclaimer
This article serves exclusively for informational intentions and lacks the intention to extend medical guidance.
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Zunnash KhanLive Science Contributor
Zunnash Khan exists as a mechatronics engineer as well as a science journalist originating from Pakistan. She has contributed writing to Science, The Scientist, and Brainfacts.org, among additional outlets.
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