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

Shimshek, Derya and Jacobson, Laura and Kolly, Carine and Zamurovic Ribrioux, Natasa and Balavenkatraman, Kamal Kumar and Morawiec, Laurent and Kreutzer, Robert and Schelle, Juliane and Jucker, Mathias and Bertschi, Barbara and Theil, Diethilde and Heier, Annabelle and Bigot, Karine and Beltz, Karen and Machauer, Rainer and Brzak, Irena and Perrot, Ludovic and Neumann, Ulf (2016) Pharmacological BACE1 and BACE2 inhibition induces hair hypopigmentation by inhibiting PMEL17 processing in mice. Scientific Reports, 6. p. 21917. ISSN 2045-2322

Abstract

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

Item Type: Article
Date Deposited: 23 Mar 2016 00:45
Last Modified: 23 Mar 2016 00:45
URI: https://oak.novartis.com/id/eprint/25908

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