Darier disease (DD) is a rare severe acantholytic skin disease caused by mutations in the ATP2A2 gene that encodes for the sarco/endoplasmic reticulum calcium ATPase isoform 2 (SERCA2). SERCA2 maintains endoplasmic reticulum calcium homeostasis by pumping calcium into the ER, critical for regulating cellular calcium dynamics and cellular function. To date, there is no treatment that specifically targets the disease mechanisms in DD. Dantrolene sodium (Dl) is a ryanodine receptor antagonist that inhibits calcium release from ER to increase ER calcium levels and is currently used for non-dermatological indications. In this study, we first identified dysregulated genes and molecular pathways in DD patient skin, demonstrating downregulation of cell adhesion and calcium homeostasis pathways, as well as upregulation of ER stress and apoptosis. We then show in various in vitro models of DD and SERCA2 inhibition that Dl aided in the retention of ER calcium and promoted cell adhesion. In addition, Dl treatment reduced ER stress and suppressed apoptosis. Our findings suggest that Dl specifically targets pathogenic mechanisms of DD and may be a potential treatment.

中文翻译：

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丹曲林可纠正达里尔病的细胞疾病特征，可能是一种新的治疗方法。


达里尔病 (DD) 是一种罕见的严重棘层松解性皮肤病，由编码肌浆/内质网钙 ATP 酶亚型 2 (SERCA2) 的 ATP2A2 基因突变引起。 SERCA2 通过将钙泵入内质网来维持内质网钙稳态，这对于调节细胞钙动力学和细胞功能至关重要。迄今为止，还没有专门针对 DD 疾病机制的治疗方法。丹曲林钠 (Dl) 是一种兰尼碱受体拮抗剂，可抑制 ER 中的钙释放以增加 ER 钙水平，目前用于非皮肤病适应症。在这项研究中，我们首先确定了 DD 患者皮肤中失调的基因和分子通路，证明了细胞粘附和钙稳态通路的下调，以及 ER 应激和细胞凋亡的上调。然后，我们在 DD 和 SERCA2 抑制的各种体外模型中表明，D1 有助于保留 ER 钙并促进细胞粘附。此外，D1治疗减少了ER应激并抑制了细胞凋亡。我们的研究结果表明，Dl 专门针对 DD 的致病机制，并且可能是一种潜在的治疗方法。