Mauro Theodora
Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
J Invest Dermatol. 2014 Jul;134(7):1800-1801. doi: 10.1038/jid.2014.97.
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.
Darier病（DD）由内质网（ER）钙ATP酶ATP2A2（蛋白SERCA2）突变引起。目前的治疗方式对许多患者无效。本报告显示，在DD角质形成细胞以及用SERCA2抑制剂毒胡萝卜素处理的正常角质形成细胞中，SERCA2功能受损会耗尽内质网钙储存，导致内质网应激持续存在，并增加对内质网应激源的敏感性。反过来，内质网应激会通过桥粒斑蛋白、桥粒芯糖蛋白3、桥粒芯胶蛋白3和E-钙黏蛋白向质膜的重新分布受损，导致细胞间黏附异常。本报告阐明了内质网钙耗竭及由此产生的内质网应激是该疾病发病机制的核心。此外，作者介绍了一种可能的新型治疗药物——米格列醇。
