Yeast-Based Screen to Identify Natural Compounds with a Potential Therapeutic Effect in Hailey-Hailey Disease

Abstract

The term orthodisease defines human disorders in which the pathogenic gene has orthologs in model organism genomes. Yeasts have been instrumental for gaining insights into the molecular basis of many human disorders, particularly those resulting from impaired cellular metabolism. We and others have used yeasts as a model system to study the molecular basis of Hailey-Hailey disease (HHD), a human blistering skin disorder caused by haploinsufficiency of the gene ATP2C1 the orthologous of the yeast gene PMR1. We observed that K. lactis cells defective for PMR1 gene share several biological similarities with HHD derived keratinocytes. Based on the conservation of ATP2C1/PMR1 function from yeast to human, here we used a yeast-based assay to screen for molecules able to influence the pleiotropy associated with PMR1 deletion. We identified six compounds, Kaempferol, Indirubin, Lappaconite, Cyclocytidine, Azomycin and Nalidixic Acid that induced different major shape phenotypes in K. lactis. These include mitochondrial and the cell-wall morphology-related phenotypes. Interestingly, a secondary assay in mammalian cells confirmed activity for Kaempferol. Indeed, this compound was also active on human keratinocytes depleted of ATP2C1 function by siRNA-treatment used as an in-vitro model of HHD. We found that Kaempferol was a potent NRF2 regulator, strongly inducing its expression and its downstream target NQO1. In addition, Kaempferol could decrease oxidative stress of ATP2C1 defective keratinocytes, characterized by reduced NRF2-expression. Our results indicated that the activation of these pathways might provide protection to the HHD-skin cells. As oxidative stress plays pivotal roles in promoting the skin lesions of Hailey-Hailey, the NRF2 pathway could be a viable therapeutic target for HHD.

Exploring Yeast as a Study Model of Pantothenate Kinase-Associated Neurodegeneration and for the Identification of Therapeutic Compounds

“…CQ CL belongs to the quinoline family and it has been demonstrated that 8-hydroxyquinoline (8HQ), its precursor, can restore metal homeostasis in models of Alzheimer’s disease [ 47 ]. Furthermore, besides its antimicrobial activity nalH is also able to complex with iron and has been found to be able to reduce the sensitivity to the ROS inducing agent menadione in a yeast model of Hailey-Hailey disease [ 58 ]. On the basis of these properties, we can speculate that the mechanism that underlies their rescue ability could lie on their property to chelate the excess iron and reducing the oxidative stress and maybe the membrane damage.…”

Current evidence to support the therapeutic potential of flavonoids in oxidative stress-related dermatoses

“…An experiment in vitro showed that naringenin could significantly reduce the production of ROS in keratinocytes of PV and relieve the decline of mitochondrial membrane potential; moreover, naringenin could not only enhance the levels of total antioxidant capacity, SOD and GSH-Px, but also inhibit nucleotide-binding oligomerization domain 2-mediated NF-κB pathway to protect HaCaT cell from OS injury or apoptosis induced by PV serum [147]. In another experiment basing on the Hailey-Hailey disease (HHD, a familial benign pemphigus) model, it was found that kaempferol effectively worked on HHD model via directly reducing OS of ATP2C1 gene defective keratinocytes and restraining the sensitivity to ROS, further to restore mitochondrial function; at the same time, kaempferol could activate the Nrf2 pathway and induce the downstream target NAD(P)H: quinone oxidoreductase 1 to mitigate OS damage and protect the skin cells [148]. Recently, Cassia fistula, a herbal drug containing flavonoids, has been discovered to be an excellent remedy of wound healing in PV due to its oxidation resistance, the underlying mechanism being associated with DPPH and hydroxyl radical reduction [149].…”

Pmr-1 gene affects susceptibility of Caenorhabditis elegans to Staphylococcus aureus infection through glycosylation and stress response pathways' alterations

“…HHD is an autosomal dominant skin disorder in which despite the association of mutation of ATP2C1 with the disease, its in vivo role remains poorly investigated [7][8][9]. The yeast model has provided important information that can explain how in Hailey-Hailey disease loss of ATP2C1 affects human keratinocytes homeostasis [10]. In yeast, inactivation of pmr-1 leads to multiple alterations, compatible with the observed defects in Ca 2+ and Mn 2+ homeostasis.…”