Dantrolene corrects cellular disease features of Darier disease and may be a novel treatment.
Cell Adhesion
Dantrolene
Darier Disease
ER Calcium
UPR
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: Germany
ID NLM: 101487380
Informations de publication
Date de publication:
26 Jul 2024
26 Jul 2024
Historique:
received:
05
06
2023
accepted:
04
07
2024
revised:
26
06
2024
medline:
27
7
2024
pubmed:
27
7
2024
entrez:
26
7
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 39060641
doi: 10.1038/s44321-024-00104-3
pii: 10.1038/s44321-024-00104-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
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