Impaired calcium signalling and neuropsychiatric disorders in Darier disease: An exploratory review

Abstract

Darier (Darier‐White) disease (DD) is an autosomal dominant skin disorder caused by pathogenic mutations in the ATP2A2 gene which encodes a calcium ATPase in the sarco‐endoplasmic reticulum (SERCA2). Defects in the SERCA2 protein lead to an impairment of cellular calcium homeostasis, which in turn, triggers cell death pathways. There is a high prevalence of neuropsychiatric disorders in patients affected by this condition, namely intellectual disability, bipolar disorder, schizophrenia, and suicidality. Though these associations have been well‐documented over the years, little has been discussed or investigated regarding the pathophysiological mechanisms. The goal of this article is to review the literature related to the most commonly associated neuropsychiatric disorders found in patients with DD, highlight the pathophysiological mechanisms underlying each condition, and examine potential interventions that may be of interest for future development. A literature search was performed using PubMed to access and review relevant articles published in the last 40 years. Keywords searched included Darier disease neuropsychiatric, Darier disease pathophysiology, SERCA2 central nervous system, SERCA 2 skin, ATP2A2 central nervous system, ATP2A2 skin, sphingosine‐1‐phosphate signalling skin, sphingosine‐1‐phosphate signalling central nervous system, P2X7 receptor skin, and P2X7 receptor central nervous system. Our search resulted in 2692 articles, of which 61 articles were ultimately included in this review.

Heat stress induces calcium dyshomeostasis to subsequent cognitive impairment through ERS-mediated apoptosis via SERCA/PERK/eIF2α pathway

“…At present, thapsigargin, a SERCA inhibitor, has become a commonly used drug to induce ERS and activate the UPR [ 19 , 20 ]. More importantly, the dysregulation of Ca 2+ homeostasis induced by SERCA is implicated in numerous pathological processes characterized by cognitive impairment as the primary clinical manifestation, including Darier’s disease, Alzheimer’s disorder, and cerebral ischemia [ 21 – 23 ]. It is believed that targeting SERCA to restore Ca 2+ homeostasis and alleviate neural apoptosis caused by ERS holds promise as a potential therapeutic strategy for neurodegenerative diseases.…”

Heat stress induces calcium dyshomeostasis to subsequent cognitive impairment through ERS-mediated apoptosis via SERCA/PERK/eIF2α pathway

“…At present, thapsigargin, a SERCA inhibitor, has become a commonly used drug to induce ERS and activate the UPR (Bian et al, 1997;Mengesdorf et al, 2001). More importantly, the dysregulation of Ca 2+ homeostasis induced by SERCA is implicated in numerous pathological processes characterized by cognitive impairment as the primary clinical manifestation, including Darier's disease, Alzheimer's disorder, and cerebral ischemia (Ambur et al, 2022;Britzolaki et al, 2020;Chemaly et al, 2018). It is believed that targeting SERCA to restore Ca 2+ homeostasis and alleviate neural apoptosis caused by ERS holds promise as a potential therapeutic strategy for neurodegenerative diseases.…”