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Published on: February 27, 2018
Complex multipathways alterations and oxidative stress are associated with Hailey-Hailey disease
S Cialfi1, C Oliviero, S Ceccarelli
1Department of Experimental Medicine, University La Sapienza, 00161, Rome, Italy.
Insights
Hailey-Hailey disease involves skin cell separation due to ATP2C1 gene mutations. This study reveals oxidative stress and altered signaling pathways like Notch1 and Itch contribute to HHD pathogenesis.
Area of Science:
- Dermatology
- Molecular Biology
- Cell Biology
Background:
- Hailey-Hailey disease (HHD) is an autosomal dominant skin disorder causing acantholysis and erosive lesions.
- Mutations in the ATP2C1 gene are linked to HHD, but the precise molecular mechanisms remain unclear.
- Understanding early signaling events in HHD pathogenesis is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate early signaling events influencing epithelial cell growth and differentiation in HHD.
- To elucidate the molecular mechanisms underlying keratinocyte dysfunction in HHD.
- To identify key molecular players and pathways involved in HHD development.
Main Methods:
- Primary keratinocytes from HHD patients were analyzed for gene and protein expression.
- Western blot and RT-PCR were used to evaluate key regulatory signals.
- Dihydrorhodamine 123 (DHR) assay assessed reactive oxygen species (ROS) accumulation.
Main Results:
- HHD keratinocytes exhibited downregulated Notch1 and altered p63 isoform expression.
- Itch protein levels were significantly decreased in HHD keratinocytes, while c-Jun remained unaffected.
- Evidence suggests HHD keratinocytes experience oxidative stress, potentially causing Notch1 and Itch downregulation.
Conclusions:
- HHD pathogenesis involves a complex interplay of altered signaling pathways.
- Oxidative stress and dysregulation of Notch1 and Itch signaling are implicated in HHD.
- These findings highlight a multi-hit molecular mechanism contributing to the diverse HHD phenotype.
Background:
Hailey-Hailey disease (HHD) is an autosomal dominant disorder characterized by suprabasal cutaneous cell separation (acantholysis) leading to the development of erosive and oozing skin lesions. While a strong relationship exists between mutations in the gene that encodes the Ca(2+)/Mn(2+)-adenosine triphosphatase ATP2C1 and HHD, we still have little understanding of how these mutations affect manifestations of the disease.
Objectives:
This study was designed to determine early signalling events that affect epithelial cell growth and differentiation during HHD development.
Methods:
Expression of key regulatory signals important for maintaining skin homeostasis were evaluated by Western blot analysis and by reverse transcriptase-polymerase chain reaction in primary keratinocytes obtained from skin biopsies of patients with HHD. Reactive oxygen species accumulation in primary keratinocytes derived from lesional skin of patients with HHD was assessed by dihydrorhodamine 123 (DHR) assay.
Results:
HHD-derived keratinocytes showed downregulation of both Notch1 and differential regulation of different p63 isoforms. Itch and p63 are co-expressed in the epidermis and in primary keratinocytes where Itch controls the p63 protein steady-state level. We found that the Itch protein was significantly decreased in HHD-derived keratinocytes whereas the expression of its target, c-Jun, remained unaffected. We also found that HHD-derived keratinocytes undergo oxidative stress, which may explain both Notch1 and Itch downregulation.
Conclusions:
Our attempt to explore the molecular mechanism underlying HHD indicates a complex puzzle in which multi-hit combinations of altered signal pathways may explain the wide spectrum of defects in HHD.
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