Nicastrin Deficiency Induces Tyrosinase-Dependent Depigmentation and Skin Inflammation

Abstract

Skin depigmentation diseases, such as vitiligo, are pigmentation disorders that often destroy melanocytes. However, their pathological mechanisms remain unclear, and therefore, promising treatments or prevention has been lacking. Here, we demonstrate that a zebrafish insertional mutant showing a significant reduction of nicastrin transcript possesses melanosome maturation defect, Tyrosinase-dependent mitochondrial swelling, and melanophore cell death. The depigmentation phenotypes are proven to be a result of g-secretase inactivation. Furthermore, live imaging demonstrates that macrophages are recruited to and can phagocytose melanophore debris. Thus, we characterize a potential zebrafish depigmentation disease model, a nicastrin hi1384 mutant, which can be used for further treatment or drug development of diseases related to skin depigmentation and/or inflammation.

Novel nicastrin mutation in hidradenitis suppurativa–Dowling–Degos disease clinical phenotype: more than just clinical overlap?

“…Preliminary experimental evidence suggests a role of NCSTN deficiency in pigmentary disorders, by modulating melanosome degradation. 5 In autoinflammatory conditions such as HS, NCSTN haploinsufficiency seems to stimulate the proliferation, type I interferon gene expression and tumour necrosis-a-induced inflammatory response of keratinocytes. 6 The fact that our patient has managed to control skin inflammation avoiding well known risk factors could have helped to detect the DDD phenotype, which could arise late in life.…”

“…The clinical and genetic overlap of HS-DDD may also have a clinical relevance, translating into a personalized therapeutic management, such as the combination of retinoids and sulfones. 8 S. Garcovich iD , 1.2 P.M. Tricarico, 3 C. Nait-Meddour, 4,5 G. Giovanardi, 1,2 K. Peris, 1,2 S. Crovella 3,6 and M. Boniotto iD…”

The fate of melanocyte: Mechanisms of cell death in vitiligo

“…Reactivation of necroptosis pathway may have therapeutic significance in metastatic melanoma due to the lack of expression of RIPK3 in melanoma tumor cells (Broussard et al., 2018). In a zebrafish vitiligo model, Nicastrin deficiency results in depigmentation with MCs featured by ruptured melanosomes, swollen mitochondria, necrotic‐like nuclei, indicating neither the classical apoptosis nor necrosis (Hsu et al., 2019). It has been demonstrated that primary MCs express high level of RIPK3 and can be induced necroptosis through CD95L‐induced MLKL phosphorylation (Geserick et al., 2015); however, according to the research of Sun.…”

Nicastrin-Like, a Novel Transmembrane Protein from Trypanosoma cruzi Associated to the Flagellar Pocket

“…As a glycosylated protein, NICT can present differences in the glycosylated sites that could allow it to assume other roles in the biochemical pathways that regulate Aβ length and response to γ-secretase modulators [8]. Furthermore, hu-NICT was suggested to be involved in different various other human pathologies [9], which include hidradenitis suppurativa [10,11], depigmentation and skin inflammation [12], as well as pancreatic cancer prognosis [13].…”