title: Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice.
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.
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Derya R
authors.initials: DR
authors.lastname: Shimshek
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Jacobson
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Carine
authors.initials: C
authors.lastname: Kolly
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Natasa
authors.initials: N
authors.lastname: Zamurovic
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Kamal Kumar
authors.initials: KK
authors.lastname: Balavenkatraman
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Morawiec
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Kreutzer
authors.affiliation: Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen and German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Schelle
authors.affiliation: Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen and German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bertschi
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Diethilde
authors.initials: D
authors.lastname: Theil
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Heier
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Karine
authors.initials: K
authors.lastname: Bigot
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Karen
authors.initials: K
authors.lastname: Beltz
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Machauer
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Irena
authors.initials: I
authors.lastname: Brzak
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Perrot
authors.affiliation: Neuroscience, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D006197:Hair / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010446:Peptide Fragments / Q000378:metabolism; D010848:Picolinic Acids / Q000494:pharmacology; D010858:Pigmentation / Q000187:drug effects; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013843:Thiazines / Q000494:pharmacology; D014602:Uvea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058951:gp100 Melanoma Antigen / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C509285:Bace2 protein, mouse; D008543:Melanins; C000605932:NB-360; D010446:Peptide Fragments; D010848:Picolinic Acids; C548642:Pmel protein, mouse; D011480:Protease Inhibitors; D012333:RNA, Messenger; D013843:Thiazines; C078592:amyloid beta-protein (1-40); D058951:gp100 Melanoma Antigen; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse