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@ARTICLE{Shimshek:138397,
      author       = {Shimshek, Derya R and Jacobson, Laura H and Kolly, Carine
                      and Zamurovic, 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},
      title        = {{P}harmacological {BACE}1 and {BACE}2 inhibition induces
                      hair depigmentation by inhibiting {PMEL}17 processing in
                      mice.},
      journal      = {Scientific reports},
      volume       = {6},
      number       = {1},
      issn         = {2045-2322},
      address      = {[London]},
      publisher    = {Macmillan Publishers Limited, part of Springer Nature},
      reportid     = {DZNE-2020-04719},
      pages        = {21917},
      year         = {2016},
      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.},
      keywords     = {Amyloid Precursor Protein Secretases: antagonists $\&$
                      inhibitors / Amyloid Precursor Protein Secretases: genetics
                      / Amyloid Precursor Protein Secretases: metabolism / Amyloid
                      beta-Peptides: metabolism / Animals / Aspartic Acid
                      Endopeptidases: antagonists $\&$ inhibitors / Aspartic Acid
                      Endopeptidases: genetics / Aspartic Acid Endopeptidases:
                      metabolism / Blotting, Western / Cell Line, Tumor / Female /
                      Hair: drug effects / Hair: metabolism / Hair: pathology /
                      Humans / Male / Melanins: metabolism / Melanocytes: cytology
                      / Melanocytes: metabolism / Mice / Mice, Inbred C57BL /
                      Mice, Knockout / Microscopy, Fluorescence / Peptide
                      Fragments: metabolism / Picolinic Acids: pharmacology /
                      Pigmentation: drug effects / Prosencephalon: metabolism /
                      Prosencephalon: pathology / Protease Inhibitors:
                      pharmacology / RNA, Messenger: metabolism / Real-Time
                      Polymerase Chain Reaction / Thiazines: pharmacology / Uvea:
                      drug effects / Uvea: metabolism / Uvea: pathology / gp100
                      Melanoma Antigen: antagonists $\&$ inhibitors / gp100
                      Melanoma Antigen: metabolism / Amyloid beta-Peptides (NLM
                      Chemicals) / Bace2 protein, mouse (NLM Chemicals) / Melanins
                      (NLM Chemicals) / NB-360 (NLM Chemicals) / Peptide Fragments
                      (NLM Chemicals) / Picolinic Acids (NLM Chemicals) / Pmel
                      protein, mouse (NLM Chemicals) / Protease Inhibitors (NLM
                      Chemicals) / RNA, Messenger (NLM Chemicals) / Thiazines (NLM
                      Chemicals) / amyloid beta-protein (1-40) (NLM Chemicals) /
                      gp100 Melanoma Antigen (NLM Chemicals) / Amyloid Precursor
                      Protein Secretases (NLM Chemicals) / Aspartic Acid
                      Endopeptidases (NLM Chemicals) / Bace1 protein, mouse (NLM
                      Chemicals)},
      cin          = {AG Jucker},
      ddc          = {600},
      cid          = {I:(DE-2719)1210001},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26912421},
      pmc          = {pmc:PMC4766495},
      doi          = {10.1038/srep21917},
      url          = {https://pub.dzne.de/record/138397},
}