TREX1 is a gene responsible for maintaining the body’s DNA. However, new research indicates that when individuals have a mutated TREX1 from birth, it leads to severe DNA damage over time. This ultimately causes a rare, deadly disease known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL). Scientists at the Perelman School of Medicine at the University of Pennsylvania led the research, which offers insight into the role of DNA damage in aging. The study provides clues to the mechanism behind RVCL and its damaging effects. It was published in Nature Communications.of the blood vessel walls,” study first author Yoshimi Nozawa said in the news release. “This discovery not only sheds light on the disease mechanism of RVCL, but also elucidates the molecular mechanism of aging in general.”
The researchers stumbled upon the connection while studying cells in the lab. When they mutated TREX1 in the lab-grown cells, they noticed a significant increase in the typical markers of DNA damage. This pointed to the conclusion that TREX1 was acting as a factor in the accelerated DNA damage process.
With this discovery, the team plans to explore potential treatment options for RVCL, as well as potential applications for the general aging process. And if aging is, in fact, related to the same process, then there could be potential for future discoveries, study senior author Koh-ichi Nagata said in the news release.
“In the blood vessel wall,” Jonathan Miner, MD, PhD, an associate professor of Rheumatology at the Perelman School of Medicine and the lead author of the study, explained. “If this is the case, then targeting TREX1 could have very broad implications for the treatment of many human diseases linked to aging, including cardiovascular diseases, autoimmune disorders, and cancer.” RVCL affects about 200 people worldwide and is often misdiagnosed as lupus, multiple sclerosis, or cancer. The disease causes the breakdown of small blood vessels in the body, which can affect many organs, including the brain, eyes, kidneys, liver, and bones. Patients with this disease may experience a wide range of symptoms and complications.Patients with the condition typically do not start experiencing symptoms until their 40s or 50s, such as memory loss, partial loss of vision, and small strokes. This can eventually lead to organ damage and failure, including brain atrophy and blindness. Unfortunately, there is currently no cure or treatment, and many patients die within five to ten years of the onset of symptoms.
“We’re optimistic that our research will lead to improvements in the lives of patients with RVCL,” said the other lead author of the study, Taisuke Kato, PhD, an associate professor of Molecular Neuroscience at Niigata University. “With our discoveries, we believe we will be much better equipped to address this condition.”equipped to address what is happening within their bodies.”
By studying RVCL models in animal and human cells, Miner and his colleagues investigated their theory that the TREX1 mutation, which shortens the gene, was causing instability within cells and damage that looks similar to breakdowns seen in radiation injuries.
Their findings revealed that the mutation was disrupting a DNA repair process, which occurs when there is a break in both strands of DNA. This disruption of the process allowed DNA to be deleted, leading to premature aging and stopped cell division, ultimately resulting in overall premature aging and organ damage.
Aside from identifying the primary mechanism of damage in RVCL, the researchers also discovered that the TREX1 mutation exhibited a cell-level vulnerability similar to those found in individuals with mutations in the BRCA1 and BRCA2 genes, which are associated with breast cancer. Indeed, the authors observed similarly increased rates of breast cancer risk in patients with TREX1 mutations as in those with mutations in the BRCA1 and BRCA2 genes.
Furthermore, the effect of the TREX1 mutation on DNA damage also renders individuals with it more susceptible to harm.The team found that in some cases, chemotherapy may have actually accelerated the progression of the disease, Miner expressed concern about this, stating that chemotherapy was often prescribed to treat suspected autoimmunity in RVCL patients, but this may have made the disease worse. The study’s findings give a better understanding of the treatments and medications that could be beneficial for people with RVCL.y, in order to provide potential treatments for RVCL, researchers are exploring options such as reducing levels of TREX1 in the body, correcting the mutation, or preventing the gene’s DNA-damaging effects. Miner also mentioned that while these therapies are being developed, they are investigating whether existing FDA-approved medications for other diseases could be repurposed for RVCL or have an impact on TREX1 levels in the body. Additionally, the study aims to understand the increase in TREX1 levels with age in various tissues in all humans, not just those with RVCL, and the related processes. This research goes beyond just RVCL patients and has broader implications.RVCL research has potential implications for the DNA damage theory of aging, according to Miner. Understanding the role of TREX1 in RVCL may lead to insights into the mechanisms linking the TREX1 gene to a range of human conditions, including normal aging. The study received funding from various sources, including the National Institutes of Health and the Rheumatology Research Foundation.The research was supported by grants from the Promotion of Science (22H00466) and the Japan MHLW for Research on Intractable Disease (JP21FC1007).
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