Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice

• DOI: 10.1038/srep21917
• Publication Date: 2016-02-25T10:34:50Z
• Authors: Derya R. Shimshek; Laura H. Jacobson; Carine Kolly; Natasa Zamurovic; Kamal Kumar Balav...; Laurent Morawiec; Robert Kreutzer; Juliane Schelle; Mathias Jucker; Barbara Bertschi; Diethilde Theil; Annabelle Heier; Karine Bigot; Karen Beltz; Rainer Machauer; Irena Brzak; Ludovic Perrot; Ulf Neumann
• Keywords: Melanosome; Melanocyte; Depigmentation; Amyloid (mycology)

Abstract Melanocytes of the hair follicle produce melanin and are essential in determining differences color. Pigment cell-specific MELanocyte Protein (PMEL17) plays a crucial role melanogenesis. One critical steps is amyloid-like functional oligomerization PMEL17. Beta Site APP Cleaving Enzyme-2 (BACE2) γ-secretase have been shown to be key players generating proteolytic fragments The β-secretase (BACE1) responsible for generation amyloid-β (Aβ) brain therefore proposed as therapeutic target Alzheimer’s disease (AD). Currently BACE1 inhibitors, most which lack selectivity over BACE2, demonstrated efficacious reduction peptides animals CSF humans. BACE2 knock-out mice deficiency PMEL17 processing leading impaired storage depigmentation. Here, we confirm BACE2-mediated inhibition vitro mouse human melanocytes. Furthermore, show that wildtype well bace2 +/− −/− treated with potent dual BACE1/BACE2 inhibitor NB-360 display dose-dependent appearance irreversibly depigmented hair. Retinal pigmented epithelium showed no morphological changes. Our data demonstrates additional affects melanosome maturation induces depigmentation mice.