Recent research has unveiled a female-specific mechanism of neurodegeneration linked to the gene KDM6A, which is located on the X chromosome and exhibits heightened expression in females compared to males. This significant finding arises from a study conducted by researchers at UCLA, published in Science Translational Medicine on October 17, 2025.
Key Findings
- A gene on the X chromosome, KDM6A, displays higher expression levels in women than in men.
- Silencing this gene in microglia (the brain's resident immune cells) in a mouse model resulted in protective effects against multiple sclerosis (MS).
- Metformin, an anti-diabetes medication, offered similar benefits, particularly in female mice.
Understanding Gender Vulnerability
Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease, predominantly affecting individuals between the ages of 20 and 40. This condition is characterized by the infiltration of immune cells, including lymphocytes and macrophages, into the central nervous system, culminating in myelin loss and neuroinflammation—crucial factors in the pathology of not just MS but also other neurodegenerative diseases such as Alzheimer’s disease [2].
Notably, the prevalence of MS in females is approximately three times higher than that in males [3]. The reasons for these gender differences have perplexed researchers for many years, but the recent UCLA study provides valuable insights into this phenomenon.
The Role of the KDM6A Gene
The research highlights that disparities in microglial function between sexes can be attributed to a combination of sex hormones and sex chromosomes. Males possess a single X chromosome, while females have two, leading to a comparative doubling of gene expressions in women, except when genes evade silencing mechanisms that typically mitigate this imbalance.
Among these is Kdm6a, which encodes a protein responsible for regulating chromatin configuration, facilitating the expression of various genes. The researchers conducted a comparative study using microglia from human samples and noted significantly higher levels of Kdm6a in female-derived cells.
Research Methodology and Results
In experiments involving a mouse model of MS, the team deleted the Kdm6a gene specifically in microglia and observed a remarkable decrease in disease severity among female mice. The outcomes included:
| Assessment Type | Results in cKO Female Mice |
|---|---|
| Disease Severity Scores | Significantly lower compared to control mice |
| Axonal Damage Markers (APP) | Decreased levels |
| Intact Axon Markers (NF200) | Increased presence |
| Myelin Preservation | Enhanced amounts observed |
The deletion of Kdm6a in microglia led to notable alterations in gene expression profiles, particularly in the context of disease-associated markers and inflammatory responses.
Effect of Metformin on Neuroprotection
Following the gene knockout experiments, the researchers introduced metformin to the study. Notably utilized for its anti-diabetic effects, metformin is also regarded for its potential geroprotective effects. The results showed that:
| Outcome | Findings in Metformin-Treated Mice |
|---|---|
| Disease Clinical Scores | Improved clinical outcomes compared to control group |
| Microglial Activation | Reduction in activation levels |
| Resting Microglial Markers | Increased presence |
These results suggest that metformin may partially mimic the neuroprotective effects expected from Kdm6a deletion, reinforcing the need for further research into its therapeutic use.
Human Relevance and Future Directions
Complementing the animal studies, human RNA sequencing also indicated that women with MS exhibited higher KDM6A expression levels and greater dysregulation of microglial genes, aligning with the earlier findings observed in the mouse model.
Dr. Rhonda Voskuhl, the lead author, stated, “These findings elucidate why women are more susceptible to neurodegenerative diseases and propose potential treatments targeting this imbalance.” The implications of this research pave the way for potential therapeutic strategies during menopause that might include estrogen treatments aimed at mitigating neurodegeneration in women.
Conclusion
In summary, the discovery of the sex-specific mechanism involving KDM6A and its relation to neuroinflammation presents a compelling avenue for future research and therapeutic interventions in diseases predominantly affecting women, such as multiple sclerosis. Understanding these mechanisms could lead to more targeted and effective treatments, ultimately improving outcomes for affected populations.
Literature Cited
[1] Yuichiro Itoh et al. Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles. (2025) Sci. Transl. Med. 17, eadq3401.
[2] Heneka, M. T., Carson, M. J., El Khoury, J., et al. (2015). Neuroinflammation in Alzheimer’s disease. The Lancet Neurology, 14(4), 388-405.
[3] Portaccio, E., Magyari, M., et al. (2024). Multiple sclerosis: emerging epidemiological trends and redefining the clinical course. The Lancet Regional Health–Europe, 44.
Discussion