Darier disease cells lose antioxidant defenses under stress, study finds
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.
Scientists at Northwestern Medicine have discovered how a genetic mutation in Darier disease weakens skin cells' ability to protect themselves from oxidative stress. This oxidative stress is a key factor in triggering the painful skin flare-ups associated with the rare disorder. The study, published in Science Advances, reveals that mutations in the ATP2A2 gene, which encodes a protein essential for calcium transport in skin cells, lead to a breakdown in the cells' antioxidant defenses.
When exposed to chemicals that generate reactive oxygen species, cells from patients with Darier disease showed significant vulnerability compared to healthy cells. These stressed cells lost their ability to maintain strong connections with neighboring cells, mirroring the tissue breakdown observed in patients. The research indicates that Darier disease cells have reduced levels of glutathione, a crucial antioxidant, and struggle to activate the pentose phosphate pathway, a cellular process that helps regenerate antioxidants.
As a result, these cells become more susceptible to oxidative damage, which weakens the protein responsible for maintaining cell-to-cell adhesion. This weakening of cell adhesion may explain why symptoms of Darier disease often develop during adolescence or early adulthood, even though the genetic mutation is present from birth.
The study also found that treatments with antioxidants, particularly N-acetylcysteine, which supports glutathione production, helped protect the patient-derived skin cells from oxidative stress. Additionally, compounds that activate the impaired SERCA2 protein improved cell function and reduced oxidative injury. Researchers hope these findings will pave the way for new therapeutic strategies targeting the antioxidant deficiencies in Darier disease, potentially offering relief to patients experiencing painful flare-ups.
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