The molecular mechanisms behind Darier's Disease: from genes to proteins

Darier Disease (DD) (OMIM #124200) is a rare autosomal dominant genodermatosis affecting around 1 in 50,000 people. From a histopathological point of view, DD is characterized by loss of intercellular adhesion (acantholysis), premature and abnormal keratinization (dyskeratosis) and presence of rounded keratinocytes (corps ronds). Skin lesions typically appear in patients between the age of 6 and 20 years, predominantly in body areas more exposed to UV irradiation, heat and friction. DD is primarily attributed to missense, non-sense, deletion, insertion and altered splicing mutations within the ATP2A2 gene (12q23-24.1) encoding the Sarco/Endoplasmic Reticulum Calcium ATPase type 2 (SERCA2), a ubiquitously expressed cellular pump responsible for the translocation of Ca2+ from the cytosol to the Endoplasmic Reticulum. Altered SERCA2 function impairs the intracellular calcium homeostasis leading to ER stress response and cell apoptosis. The perturbation of calcium levels could be responsible for desmosomes assembly alteration, consequently impairing cell-to-cell adhesion. However, the molecular mechanism by which SERCA2 mutations cause disease abnormalities is not well clarified. Considering the SERCA2 role in the modulation of the NOTCH1 pathway in several disease models, our hypothesis posits that SERCA2 loss-of-function variants could inactivate NOTCH1 activity and its signaling. The project's aims include the definition of the role of SERCA2 mutations on the NOTCH1 and other molecular pathways and the transcriptional effects of SERCA2 inhibition. By combining in vitro and in vivo assays we identified novel signaling pathways deregulations. In particular, upregulated ones included immunological, inflammatory, and cell responses to external stimuli, while genes associated with metabolic functions such as fatty acid metabolism, ribosomal structural components, and mitochondrial activity resulted to be downregulated. Additionally, NOTCH1 signaling target proteins were found to be dysregulated, according to our starting hypothesis. Our findings provide important insights into the molecular mechanisms underlying Darier disease, which may offer potential targets for therapeutic interventions.