Northwestern Medicine scientists have uncovered a mechanism that may explain why people with Darier disease, a rare genetic skin disorder, often develop symptoms years after birth and experience painful flare-ups triggered by heat, sunlight and psychological stress
The findings, published in Science Advances, point to oxidative stress and impaired cellular defenses as central drivers of Darier disease. The study also suggests potential therapeutic approaches using antioxidants, said Robert Harmon, PhD, research assistant professor of Pathology, who was first author of the study
In the study, Harmon and investigators in the laboratory of Kathleen Green, PhD, the Joseph L. Mayberry, Sr., Professor of Pathology and Toxicology, 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
“One unique thing about this study is that it was funded by a family directly affected by this rare skin disease ,” Harmon said. “What we found is that one of the common denominators of the triggers of a disease flare-up is oxidative stress.”
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, Harmon said
To better understand what triggers disease flare-ups, 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
The stressed Darier disease cells proved far more vulnerable than healthy skin cells, the study found. 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,” 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
“What the Darier disease cells were deficient in was one of the biggest self-made antioxidants in our cells called glutathione,” Harmon said
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, Harmon said
The findings may also explain why symptoms appear later in life, despite the mutation being present from birth
“Kids are born with this mutation, and they’re fine,” Harmon said. “The mutation in and of itself is not enough to really cause the skin to fall apart.”
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
“We added ectopic antioxidants to the dish. We loaded them up with something called N-acetylcysteine, and that basically protected the cells,” Harmon said
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,” Harmon said
Beyond its therapeutic implications, Harmon said the project has benefited from an especially close partnership with patients and families affected by the disease
“It’s been really heartening to see the response that we get from patients, really from all over the world,” Harmon said. “That’s been an important part of this.”
The study was funded by The Lee Family Philanthropic Fund, as well as National Institutes of Health (NIH) grants (R01AR041836, R01AR043380, R01CA228196, R01NS057499 R35NS132349, R01AR44619, R01AR068375, R03AR082896, R03TR005428 and P30-AR075043)
