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@ARTICLE{Njavro:145058,
      author       = {Njavro, Jasenka and Klotz, Jakob and Dislich, Bastian and
                      Wanngren, Johanna and Shmueli, Merav and Herber, Julia and
                      Kuhn, Peer-Hendrik and Kumar, Rohit and Koeglsperger, Thomas
                      and Conrad, Marcus and Wurst, Wolfgang and Feederle, Regina
                      and Vlachos, Andreas and Michalakis, Stylianos and Jedlicka,
                      Peter and Müller, Stephan A and Lichtenthaler, Stefan F},
      title        = {{M}ouse brain proteomics establishes {MDGA}1 and {CACHD}1
                      as in vivo substrates of the {A}lzheimer protease {BACE}1.},
      journal      = {The FASEB journal},
      volume       = {34},
      number       = {2},
      issn         = {0892-6638},
      address      = {Hoboken, NJ},
      publisher    = {Wiley},
      reportid     = {DZNE-2020-00417},
      pages        = {2465-2482},
      year         = {2020},
      abstract     = {The protease beta-site APP cleaving enzyme 1 (BACE1) has
                      fundamental functions in the nervous system. Its inhibition
                      is a major therapeutic approach in Alzheimer's disease,
                      because BACE1 cleaves the amyloid precursor protein (APP),
                      thereby catalyzing the first step in the generation of the
                      pathogenic amyloid beta (Aβ) peptide. Yet, BACE1 cleaves
                      numerous additional membrane proteins besides APP. Most of
                      these substrates have been identified in vitro, but only few
                      were further validated or characterized in vivo. To identify
                      BACE1 substrates with in vivo relevance, we used isotope
                      label-based quantitative proteomics of wild type and
                      BACE1-deficient (BACE1 KO) mouse brains. This approach
                      identified known BACE1 substrates, including Close homolog
                      of L1 and contactin-2, which were found to be enriched in
                      the membrane fraction of BACE1 KO brains. VWFA and cache
                      domain-containing protein 1 (CACHD)1 and MAM
                      domain-containing glycosylphosphatidylinositol anchor
                      protein 1 (MDGA1), which have functions in synaptic
                      transmission, were identified and validated as new BACE1
                      substrates in vivo by immunoblots using primary neurons and
                      mouse brains. Inhibition or deletion of BACE1 from primary
                      neurons resulted in a pronounced inhibition of substrate
                      cleavage and a concomitant increase in full-length protein
                      levels of CACHD1 and MDGA1. The BACE1 cleavage site in both
                      proteins was determined to be located within the
                      juxtamembrane domain. In summary, this study identifies and
                      validates CACHD1 and MDGA1 as novel in vivo substrates for
                      BACE1, suggesting that cleavage of both proteins may
                      contribute to the numerous functions of BACE1 in the nervous
                      system.},
      keywords     = {Alzheimer Disease: genetics / Alzheimer Disease: metabolism
                      / Alzheimer Disease: pathology / Amyloid Precursor Protein
                      Secretases: genetics / Amyloid Precursor Protein Secretases:
                      metabolism / Animals / Aspartic Acid Endopeptidases:
                      genetics / Aspartic Acid Endopeptidases: metabolism / Brain:
                      metabolism / Brain: pathology / Mice / Mice, Knockout /
                      Neural Cell Adhesion Molecules: genetics / Neural Cell
                      Adhesion Molecules: metabolism / Proteomics},
      cin          = {AG Lichtenthaler / Tübingen Pre 2020 / AG Höglinger 1 /
                      AG Wurst / AG Feederle / AG Haass old},
      ddc          = {570},
      cid          = {I:(DE-2719)1110006 / I:(DE-2719)6000018 /
                      I:(DE-2719)1110002 / I:(DE-2719)1140001 / I:(DE-2719)1140004
                      / I:(DE-2719)1110007},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342) / 344
                      - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31908000},
      doi          = {10.1096/fj.201902347R},
      url          = {https://pub.dzne.de/record/145058},
}