Home > Publications Database > Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice. > print

001     138397
005     20240321220427.0
024 7 _ |a 10.1038/srep21917
|2 doi
024 7 _ |a pmid:26912421
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024 7 _ |a pmc:PMC4766495
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037 _ _ |a DZNE-2020-04719
041 _ _ |a English
082 _ _ |a 600
100 1 _ |a Shimshek, Derya R
|0 P:(DE-HGF)0
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|e Corresponding author
245 _ _ |a Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice.
260 _ _ |a [London]
|c 2016
|b Macmillan Publishers Limited, part of Springer Nature
264 _ 1 |3 online
|2 Crossref
|b Springer Science and Business Media LLC
|c 2016-02-25
264 _ 1 |3 print
|2 Crossref
|b Springer Science and Business Media LLC
|c 2016-02-01
336 7 _ |a article
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336 7 _ |a Output Types/Journal article
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336 7 _ |a Journal Article
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336 7 _ |a ARTICLE
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336 7 _ |a JOURNAL_ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
536 _ _ |a 342 - Disease Mechanisms and Model Systems (POF3-342)
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542 _ _ |i 2016-02-01
|2 Crossref
|u https://creativecommons.org/licenses/by/4.0
588 _ _ |a Dataset connected to CrossRef, PubMed,
650 _ 7 |a Amyloid beta-Peptides
|2 NLM Chemicals
650 _ 7 |a Bace2 protein, mouse
|2 NLM Chemicals
650 _ 7 |a Melanins
|2 NLM Chemicals
650 _ 7 |a NB-360
|2 NLM Chemicals
650 _ 7 |a Peptide Fragments
|2 NLM Chemicals
650 _ 7 |a Picolinic Acids
|2 NLM Chemicals
650 _ 7 |a Pmel protein, mouse
|2 NLM Chemicals
650 _ 7 |a Protease Inhibitors
|2 NLM Chemicals
650 _ 7 |a RNA, Messenger
|2 NLM Chemicals
650 _ 7 |a Thiazines
|2 NLM Chemicals
650 _ 7 |a amyloid beta-protein (1-40)
|2 NLM Chemicals
650 _ 7 |a gp100 Melanoma Antigen
|2 NLM Chemicals
650 _ 7 |a Amyloid Precursor Protein Secretases
|0 EC 3.4.-
|2 NLM Chemicals
650 _ 7 |a Aspartic Acid Endopeptidases
|0 EC 3.4.23.-
|2 NLM Chemicals
650 _ 7 |a Bace1 protein, mouse
|0 EC 3.4.23.46
|2 NLM Chemicals
650 _ 2 |a Amyloid Precursor Protein Secretases: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases: genetics
|2 MeSH
650 _ 2 |a Amyloid Precursor Protein Secretases: metabolism
|2 MeSH
650 _ 2 |a Amyloid beta-Peptides: metabolism
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: genetics
|2 MeSH
650 _ 2 |a Aspartic Acid Endopeptidases: metabolism
|2 MeSH
650 _ 2 |a Blotting, Western
|2 MeSH
650 _ 2 |a Cell Line, Tumor
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Hair: drug effects
|2 MeSH
650 _ 2 |a Hair: metabolism
|2 MeSH
650 _ 2 |a Hair: pathology
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Melanins: metabolism
|2 MeSH
650 _ 2 |a Melanocytes: cytology
|2 MeSH
650 _ 2 |a Melanocytes: metabolism
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
650 _ 2 |a Microscopy, Fluorescence
|2 MeSH
650 _ 2 |a Peptide Fragments: metabolism
|2 MeSH
650 _ 2 |a Picolinic Acids: pharmacology
|2 MeSH
650 _ 2 |a Pigmentation: drug effects
|2 MeSH
650 _ 2 |a Prosencephalon: metabolism
|2 MeSH
650 _ 2 |a Prosencephalon: pathology
|2 MeSH
650 _ 2 |a Protease Inhibitors: pharmacology
|2 MeSH
650 _ 2 |a RNA, Messenger: metabolism
|2 MeSH
650 _ 2 |a Real-Time Polymerase Chain Reaction
|2 MeSH
650 _ 2 |a Thiazines: pharmacology
|2 MeSH
650 _ 2 |a Uvea: drug effects
|2 MeSH
650 _ 2 |a Uvea: metabolism
|2 MeSH
650 _ 2 |a Uvea: pathology
|2 MeSH
650 _ 2 |a gp100 Melanoma Antigen: antagonists & inhibitors
|2 MeSH
650 _ 2 |a gp100 Melanoma Antigen: metabolism
|2 MeSH
700 1 _ |a Jacobson, Laura H
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700 1 _ |a Kolly, Carine
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700 1 _ |a Zamurovic, Natasa
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700 1 _ |a Balavenkatraman, Kamal Kumar
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700 1 _ |a Morawiec, Laurent
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700 1 _ |a Kreutzer, Robert
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700 1 _ |a Theil, Diethilde
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700 1 _ |a Heier, Annabelle
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700 1 _ |a Bigot, Karine
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700 1 _ |a Beltz, Karen
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700 1 _ |a Machauer, Rainer
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700 1 _ |a Brzak, Irena
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700 1 _ |a Perrot, Ludovic
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700 1 _ |a Neumann, Ulf
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773 1 8 |a 10.1038/srep21917
|b : Springer Science and Business Media LLC, 2016-02-01
|n 1
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|v 6
|y 2016
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773 _ _ |a 10.1038/srep21917
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856 4 _ |u https://www.nature.com/articles/srep21917
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Marc 21