Oxidative stress drives flares in Darier disease

Robert Harmon, PhD, research assistant professor of Pathology. Photo courtesy Northwestern University

Researchers have identified a mechanism that may explain why people with the genetic skin disorder Darier disease often develop symptoms years after birth and experience painful flares triggered by heat, sunlight, and psychological stress.

The findings, published in Science Advances, point to oxidative stress and impaired cellular defences as central drivers of Darier disease. The study also suggests potential therapeutic approaches using antioxidants, said the study’s first author, Robert Harmon, PhD, in a press release. Dr. Harmon is a research assistant professor of Pathology at Northwestern University in Evanston, Ill.

In the study, Dr. Harmon and his colleagues examined skin cells from patients with Darier disease, an inherited disorder caused by mutations in the ATP2A2 gene. The gene encodes SERCA2, a protein that pumps calcium inside cells and is essential for healthy skin cell adhesion.

While scientists have known for more than two decades that mutations in ATP2A2 cause Darier disease, exactly how those mutations lead to blistering skin lesions and disease flares remained unclear.

Darier disease typically emerges during adolescence or early adulthood, and patients often experience recurrent skin blistering, infections, and painful lesions that worsen with sun exposure, heat, and stress. Existing treatments, including retinoids, can have significant side effects and are not consistently effective, Dr. Harmon said.

To better understand what triggers disease flares, the team developed a laboratory model using skin cells from patients with Darier disease. The investigators exposed the cells to chemicals that generate reactive oxygen species, mimicking oxidative stress caused by environmental and physiological triggers.

During the stress experiments, cell-to-cell connections weakened, and the cells lost the ability to maintain strong attachments, reproducing the type of tissue breakdown seen in patients.

“The Darier disease cells, compared to the control cells, were way more sensitive to this treatment, this stressor,” Dr. Harmon said. “The cells really fell apart in our dishes.”

The investigators then analyzed the cells’ metabolism and found deficiencies in a critical cellular system that helps regenerate antioxidants, called the pentose phosphate pathway. Darier disease cells contained reduced levels of glutathione, one of the body’s most important naturally produced antioxidants, the study found.

According to the study, the cells struggled to activate the pentose phosphate pathway in response to stress. As a result, they were less able to replenish glutathione and protect themselves from oxidative damage. This antioxidant deficiency leaves the remaining functional SERCA2 protein vulnerable to oxidation and inactivation, creating a cascade that eventually causes skin cells to separate from one another, Dr. Harmon said.

The findings may also explain why symptoms appear later in life, despite the mutation being present from birth.

Additionally, the team found that antioxidant treatments helped protect patient-derived cells. Adding N-acetylcysteine, a compound that supports glutathione production, preserved cell adhesion and reduced damage caused by oxidative stress. The scientists also found that compounds designed to activate SERCA2 improved cell function and reduced signs of oxidative injury.

The work has already opened the door to additional studies aimed at identifying therapies that could be rapidly translated to patients, Harmon said.

“We’re already starting to move on and using these discoveries to start testing panels of FDA-approved drugs to see if there’s anything out there already that could provide powerful protection to these cells,” Dr. Harmon said.