Darier Disease and Neuropsychiatric Illness: A Dermatologic Condition That Is More Than Skin Deep

Hua, Phoebe T.; Caplan, Jason P.

doi:10.1016/j.psym.2019.07.008

Cited by 4 publications

(3 citation statements)

References 11 publications

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“…Since calcium is a major second messenger regulating diverse biological functions including skeletal muscle contraction, cardiac pacing, neurotransmitter release, and apoptosis in many cell types (84,85), compounds affecting intracellular calcium may have a narrow therapeutic window. In fact, coincidence of neuropsychiatric and cardiac disease with DD (6, 86) implies a role beyond the skin for SERCA2 (87), including in higher-order cognition and behavior (88)(89)(90).…”

Section: Discussionmentioning

confidence: 99%

Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease

Zaver

Sarkar

Egolf

et al. 2023

Preprint

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Mutation of the ATP2A2 gene encoding sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) was linked to Darier disease more than two decades ago; however, there remain no targeted therapies for this disorder causing recurrent skin blistering and infections. Since Atp2a2 knockout mice do not phenocopy its pathology, we established a human tissue model of Darier disease to elucidate its pathogenesis and identify potential therapies. Leveraging CRISPR/Cas9, we generated human keratinocytes lacking SERCA2, which replicated features of Darier disease, including weakened intercellular adhesion and defective differentiation in organotypic epidermis. To identify pathogenic drivers downstream of SERCA2 depletion, we performed RNA sequencing and proteomic analysis. SERCA2-deficient keratinocytes lacked desmosomal and cytoskeletal proteins required for epidermal integrity and exhibited excess MAP kinase signaling, which modulates keratinocyte adhesion and differentiation. Immunostaining patient biopsies substantiated these findings with lesions showing keratin deficiency, cadherin mis-localization, and ERK hyper-phosphorylation. Dampening ERK activity with MEK inhibitors rescued adhesive protein expression and restored keratinocyte sheet integrity despite SERCA2 depletion or chemical inhibition. In sum, coupling multi-omic analysis with human organotypic epidermis as a pre-clinical model, we found that SERCA2 haploinsufficiency disrupts critical adhesive components in keratinocytes via ERK signaling and identified MEK inhibition as a treatment strategy for Darier disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease

Zaver

Sarkar

Egolf

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Since calcium is a major second messenger regulating diverse biological functions, including skeletal muscle contraction, cardiac pacing, neurotransmitter release, and apoptosis in many cell types (87,88), compounds affecting intracellular calcium may have a narrow therapeutic window. In fact, coincidence of neuropsychiatric and cardiac disease with DD (6, 89) implies a role beyond the skin for SERCA2 (90), including in higher order cognition and behavior (91)(92)(93).…”

Section: Discussionmentioning

confidence: 99%

Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease

Zaver¹,

Sarkar²,

Egolf³

et al. 2023

JCI Insight

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Mutation of the ATP2A2 gene encoding sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) was linked to Darier disease more than 2 decades ago; however, there remain no targeted therapies for this disorder causing recurrent skin blistering and infections. Since Atp2a2 -knockout mice do not phenocopy its pathology, we established a human tissue model of Darier disease to elucidate its pathogenesis and identify potential therapies. Leveraging CRISPR/Cas9, we generated human keratinocytes lacking SERCA2, which replicated features of Darier disease, including weakened intercellular adhesion and defective differentiation in organotypic epidermis. To identify pathogenic drivers downstream of SERCA2 depletion, we performed RNA sequencing and proteomics analysis. SERCA2-deficient keratinocytes lacked desmosomal and cytoskeletal proteins required for epidermal integrity and exhibited excess MAPK signaling, which modulates keratinocyte adhesion and differentiation. Immunostaining patient biopsies substantiated these findings, with lesions showing keratin deficiency, cadherin mislocalization, and ERK hyperphosphorylation. Dampening ERK activity with MEK inhibitors rescued adhesive protein expression and restored keratinocyte sheet integrity despite SERCA2 depletion or chemical inhibition. In sum, coupling multiomic analysis with human organotypic epidermis as a preclinical model, we found that SERCA2 haploinsufficiency disrupts critical adhesive components in keratinocytes via ERK signaling and identified MEK inhibition as a treatment strategy for Darier disease.

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“…7 Cannabinoids can also mediate the reactivation of latent HSV. 8 Psychiatric comorbidities, mainly mood disorders, have been clearly associated with DD 9 ; therefore, the immunosuppressive influence by cannabinoids may be underrecognized in DD, as the association between mood disorders and substance abuse is well known. Dermatologists should be well conscious of it.…”

mentioning

confidence: 99%

Kaposi‐Juliusberg Varicelliform Eruption complicating Darier disease: May cannabinoid abuse be an underestimated risk factor?

Russo

Labate

Cozzani

et al. 2021

Clinical Case Reports

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Darier Disease and Neuropsychiatric Illness: A Dermatologic Condition That Is More Than Skin Deep

Cited by 4 publications

References 11 publications

Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease

Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease

Targeting SERCA2 in organotypic epidermis reveals MEK inhibition as a therapeutic strategy for Darier disease

Kaposi‐Juliusberg Varicelliform Eruption complicating Darier disease: May cannabinoid abuse be an underestimated risk factor?

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