title: Endoplasmic reticulum calcium, stress, and cell-to-cell adhesion.
abstract: Darier's disease (DD) is caused by mutations in the endoplasmic reticulum (ER) Ca2+ ATPase ATP2A2 (protein SERCA2). Current treatment modalities are ineffective for many patients. This report shows that impaired SERCA2 function, both in DD keratinocytes and in normal keratinocytes treated with the SERCA2-inhibitor thapsigargin, depletes ER Ca2+ stores, leading to constitutive ER stress and increased sensitivity to ER stressors. ER stress, in turn, leads to abnormal cell-to-cell adhesion via impaired redistribution of desmoplakin, desmoglein 3, desmocollin 3, and E-cadherin to the plasma membrane. This report illustrates how ER Ca2+ depletion and the resulting ER stress are central to the pathogenesis of the disease. Additionally, the authors introduce a possible new therapeutic agent, miglustat.
authors.affiliation: Department of Dermatology, University of California, San Francisco, San Francisco, California, USA. Electronic address: maurot@derm.ucsf.edu.
authors.forename: Theodora
authors.initials: T
authors.lastname: Mauro
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology*; D007644:Darier Disease; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*
chemical_list: D017485:1-Deoxynojirimycin; C059896:miglustat; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human