Ricerc@Sapienza

Hailey-Hailey's disease (HHD) is a skin disease linked to mutations in ATP2C1 gene encoding Ca2+/Mn2+ ATPase localized on the Golgi; deregulations of this protein function are responsible for defects in the control of cytoplasmatic calcium concentrations leading to alterations of the desmosomic junctions and to the loss of adhesion between epidermal keratinocytes. The disorder is manifested as blistering skin lesions that do not heal and susceptible to microbial infections. While a strong relationship exists between mutations in ATP2C1 gene and HHD, the precise mechanism through which mutations induce skin lesions is unknown. We need to expand our understandings on the role of ATP2C1 in skin biology, in order to delineate how its loss may contribute to HHD. Oxidative stress plays an important role in HHD manifestation; in particular, it was found that ATP2C1 defective keratinocytes are characterized by massive ROS production and alterated Notch 1 signaling. Notch 1 signaling influences many aspects of the skin homeostasis including differentiation and wound repair. The understandings of the relevant pathways influenced by oxidative-stress would provide perspectives for future novel pharmacological targets. HHD skin lesions do not heal and show recurrent infections, indicating that HHD keratinocytes might not respond well to challenges such as wounding or infection. The success of wound healing process depends on growth factors, cytokines and chemokines involved in cellular processes. HHD lesions are characterized by deregulated cytokine expression and decreased repair properties and, moreover, HHD patients have an increased susceptibility to skin infections. It could be important investigate the influence of deregulated cytokines on ATP2C1-defective keratinocytes proliferation, differentiation and wound repair mechanisms also in order to understand if the persistent bacterial colonization is a consequence of an attenuated immune response.