TY  - JOUR
AU  - Shimshek, Derya R
AU  - Jacobson, Laura H
AU  - Kolly, Carine
AU  - Zamurovic, Natasa
AU  - Balavenkatraman, Kamal Kumar
AU  - Morawiec, Laurent
AU  - Kreutzer, Robert
AU  - Schelle, Juliane
AU  - Jucker, Mathias
AU  - Bertschi, Barbara
AU  - Theil, Diethilde
AU  - Heier, Annabelle
AU  - Bigot, Karine
AU  - Beltz, Karen
AU  - Machauer, Rainer
AU  - Brzak, Irena
AU  - Perrot, Ludovic
AU  - Neumann, Ulf
TI  - Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice.
JO  - Scientific reports
VL  - 6
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DZNE-2020-04719
SP  - 21917
PY  - 2016
AB  - 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.
KW  - Amyloid Precursor Protein Secretases: antagonists & inhibitors
KW  - Amyloid Precursor Protein Secretases: genetics
KW  - Amyloid Precursor Protein Secretases: metabolism
KW  - Amyloid beta-Peptides: metabolism
KW  - Animals
KW  - Aspartic Acid Endopeptidases: antagonists & inhibitors
KW  - Aspartic Acid Endopeptidases: genetics
KW  - Aspartic Acid Endopeptidases: metabolism
KW  - Blotting, Western
KW  - Cell Line, Tumor
KW  - Female
KW  - Hair: drug effects
KW  - Hair: metabolism
KW  - Hair: pathology
KW  - Humans
KW  - Male
KW  - Melanins: metabolism
KW  - Melanocytes: cytology
KW  - Melanocytes: metabolism
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Knockout
KW  - Microscopy, Fluorescence
KW  - Peptide Fragments: metabolism
KW  - Picolinic Acids: pharmacology
KW  - Pigmentation: drug effects
KW  - Prosencephalon: metabolism
KW  - Prosencephalon: pathology
KW  - Protease Inhibitors: pharmacology
KW  - RNA, Messenger: metabolism
KW  - Real-Time Polymerase Chain Reaction
KW  - Thiazines: pharmacology
KW  - Uvea: drug effects
KW  - Uvea: metabolism
KW  - Uvea: pathology
KW  - gp100 Melanoma Antigen: antagonists & inhibitors
KW  - gp100 Melanoma Antigen: metabolism
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Bace2 protein, mouse (NLM Chemicals)
KW  - Melanins (NLM Chemicals)
KW  - NB-360 (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
KW  - Picolinic Acids (NLM Chemicals)
KW  - Pmel protein, mouse (NLM Chemicals)
KW  - Protease Inhibitors (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - Thiazines (NLM Chemicals)
KW  - amyloid beta-protein (1-40) (NLM Chemicals)
KW  - gp100 Melanoma Antigen (NLM Chemicals)
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Aspartic Acid Endopeptidases (NLM Chemicals)
KW  - Bace1 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26912421
C2  - pmc:PMC4766495
DO  - DOI:10.1038/srep21917
UR  - https://pub.dzne.de/record/138397
ER  -