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000138397 0247_ $$2doi$$a10.1038/srep21917
000138397 0247_ $$2pmid$$apmid:26912421
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000138397 1001_ $$0P:(DE-HGF)0$$aShimshek, Derya R$$b0$$eCorresponding author
000138397 245__ $$aPharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice.
000138397 260__ $$a[London]$$bMacmillan Publishers Limited, part of Springer Nature$$c2016
000138397 264_1 $$2Crossref$$3online$$bSpringer Science and Business Media LLC$$c2016-02-25
000138397 264_1 $$2Crossref$$3print$$bSpringer Science and Business Media LLC$$c2016-02-01
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000138397 520__ $$aMelanocytes of the hair follicle produce melanin and are essential in determining the differences in hair color. Pigment cell-specific MELanocyte Protein (PMEL17) plays a crucial role in melanogenesis. One of the critical steps is the amyloid-like functional oligomerization of PMEL17. Beta Site APP Cleaving Enzyme-2 (BACE2) and γ-secretase have been shown to be key players in generating the proteolytic fragments of PMEL17. The β-secretase (BACE1) is responsible for the generation of amyloid-β (Aβ) fragments in the brain and is therefore proposed as a therapeutic target for Alzheimer's disease (AD). Currently BACE1 inhibitors, most of which lack selectivity over BACE2, have demonstrated efficacious reduction of amyloid-β peptides in animals and the CSF of humans. BACE2 knock-out mice have a deficiency in PMEL17 proteolytic processing leading to impaired melanin storage and hair depigmentation. Here, we confirm BACE2-mediated inhibition of PMEL17 proteolytic processing in vitro in mouse and human melanocytes. Furthermore, we show that wildtype as well as bace2(+/-) and bace2(-/-) mice treated with a potent dual BACE1/BACE2 inhibitor NB-360 display dose-dependent appearance of irreversibly depigmented hair. Retinal pigmented epithelium showed no morphological changes. Our data demonstrates that BACE2 as well as additional BACE1 inhibition affects melanosome maturation and induces hair depigmentation in mice.
000138397 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000138397 542__ $$2Crossref$$i2016-02-01$$uhttps://creativecommons.org/licenses/by/4.0
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000138397 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000138397 650_7 $$2NLM Chemicals$$aBace2 protein, mouse
000138397 650_7 $$2NLM Chemicals$$aMelanins
000138397 650_7 $$2NLM Chemicals$$aNB-360
000138397 650_7 $$2NLM Chemicals$$aPeptide Fragments
000138397 650_7 $$2NLM Chemicals$$aPicolinic Acids
000138397 650_7 $$2NLM Chemicals$$aPmel protein, mouse
000138397 650_7 $$2NLM Chemicals$$aProtease Inhibitors
000138397 650_7 $$2NLM Chemicals$$aRNA, Messenger
000138397 650_7 $$2NLM Chemicals$$aThiazines
000138397 650_7 $$2NLM Chemicals$$aamyloid beta-protein (1-40)
000138397 650_7 $$2NLM Chemicals$$agp100 Melanoma Antigen
000138397 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases
000138397 650_7 $$0EC 3.4.23.-$$2NLM Chemicals$$aAspartic Acid Endopeptidases
000138397 650_7 $$0EC 3.4.23.46$$2NLM Chemicals$$aBace1 protein, mouse
000138397 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: antagonists & inhibitors
000138397 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: genetics
000138397 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: metabolism
000138397 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000138397 650_2 $$2MeSH$$aAnimals
000138397 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: antagonists & inhibitors
000138397 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: genetics
000138397 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: metabolism
000138397 650_2 $$2MeSH$$aBlotting, Western
000138397 650_2 $$2MeSH$$aCell Line, Tumor
000138397 650_2 $$2MeSH$$aFemale
000138397 650_2 $$2MeSH$$aHair: drug effects
000138397 650_2 $$2MeSH$$aHair: metabolism
000138397 650_2 $$2MeSH$$aHair: pathology
000138397 650_2 $$2MeSH$$aHumans
000138397 650_2 $$2MeSH$$aMale
000138397 650_2 $$2MeSH$$aMelanins: metabolism
000138397 650_2 $$2MeSH$$aMelanocytes: cytology
000138397 650_2 $$2MeSH$$aMelanocytes: metabolism
000138397 650_2 $$2MeSH$$aMice
000138397 650_2 $$2MeSH$$aMice, Inbred C57BL
000138397 650_2 $$2MeSH$$aMice, Knockout
000138397 650_2 $$2MeSH$$aMicroscopy, Fluorescence
000138397 650_2 $$2MeSH$$aPeptide Fragments: metabolism
000138397 650_2 $$2MeSH$$aPicolinic Acids: pharmacology
000138397 650_2 $$2MeSH$$aPigmentation: drug effects
000138397 650_2 $$2MeSH$$aProsencephalon: metabolism
000138397 650_2 $$2MeSH$$aProsencephalon: pathology
000138397 650_2 $$2MeSH$$aProtease Inhibitors: pharmacology
000138397 650_2 $$2MeSH$$aRNA, Messenger: metabolism
000138397 650_2 $$2MeSH$$aReal-Time Polymerase Chain Reaction
000138397 650_2 $$2MeSH$$aThiazines: pharmacology
000138397 650_2 $$2MeSH$$aUvea: drug effects
000138397 650_2 $$2MeSH$$aUvea: metabolism
000138397 650_2 $$2MeSH$$aUvea: pathology
000138397 650_2 $$2MeSH$$agp100 Melanoma Antigen: antagonists & inhibitors
000138397 650_2 $$2MeSH$$agp100 Melanoma Antigen: metabolism
000138397 7001_ $$0P:(DE-HGF)0$$aJacobson, Laura H$$b1
000138397 7001_ $$0P:(DE-HGF)0$$aKolly, Carine$$b2
000138397 7001_ $$0P:(DE-HGF)0$$aZamurovic, Natasa$$b3
000138397 7001_ $$0P:(DE-HGF)0$$aBalavenkatraman, Kamal Kumar$$b4
000138397 7001_ $$0P:(DE-HGF)0$$aMorawiec, Laurent$$b5
000138397 7001_ $$0P:(DE-HGF)0$$aKreutzer, Robert$$b6
000138397 7001_ $$0P:(DE-2719)2811018$$aSchelle, Juliane$$b7$$udzne
000138397 7001_ $$0P:(DE-2719)2000010$$aJucker, Mathias$$b8$$udzne
000138397 7001_ $$0P:(DE-HGF)0$$aBertschi, Barbara$$b9
000138397 7001_ $$0P:(DE-HGF)0$$aTheil, Diethilde$$b10
000138397 7001_ $$0P:(DE-HGF)0$$aHeier, Annabelle$$b11
000138397 7001_ $$0P:(DE-HGF)0$$aBigot, Karine$$b12
000138397 7001_ $$0P:(DE-HGF)0$$aBeltz, Karen$$b13
000138397 7001_ $$0P:(DE-HGF)0$$aMachauer, Rainer$$b14
000138397 7001_ $$0P:(DE-HGF)0$$aBrzak, Irena$$b15
000138397 7001_ $$0P:(DE-HGF)0$$aPerrot, Ludovic$$b16
000138397 7001_ $$0P:(DE-HGF)0$$aNeumann, Ulf$$b17
000138397 77318 $$2Crossref$$3journal-article$$a10.1038/srep21917$$b : Springer Science and Business Media LLC, 2016-02-01$$n1$$p21917$$tScientific Reports$$v6$$x2045-2322$$y2016
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000138397 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766495
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