Endoplasmic reticulum calcium, stress, and cell-to-cell adhesion.

Area of Science:

• Cell Biology
• Dermatology
• Biochemistry

Background:

• Darier's disease (DD) is a genetic skin disorder caused by mutations in the ATP2A2 gene, affecting the SERCA2 pump.
• Current treatments for Darier's disease offer limited efficacy for many patients.

Purpose of the Study:

• To elucidate the role of endoplasmic reticulum (ER) calcium (Ca2+) depletion and ER stress in Darier's disease pathogenesis.
• To investigate the impact of impaired SERCA2 function on keratinocyte adhesion.
• To explore miglustat as a potential therapeutic agent for Darier's disease.

Main Methods:

• Examined SERCA2 function in Darier's disease keratinocytes and normal keratinocytes treated with thapsigargin.
• Assessed ER Ca2+ stores, ER stress markers, and the localization of key cell adhesion molecules (desmoplakin, desmoglein 3, desmocollin 3, E-cadherin).

Main Results:

• Impaired SERCA2 function leads to depletion of ER Ca2+ stores, causing constitutive ER stress and increased sensitivity to ER stressors.
• ER stress disrupts the proper redistribution of desmoplakin, desmoglein 3, desmocollin 3, and E-cadherin to the plasma membrane, impairing cell-to-cell adhesion.
• Miglustat was identified as a potential therapeutic agent.

Conclusions:

• ER Ca2+ depletion and subsequent ER stress are central mechanisms in Darier's disease pathogenesis.
• Abnormalities in cell adhesion are a direct consequence of ER stress in this condition.
• Miglustat shows promise as a novel therapeutic strategy for Darier's disease.