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000145058 1001_ $$0P:(DE-2719)2811277$$aNjavro, Jasenka$$b0$$eFirst author$$udzne
000145058 245__ $$aMouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1.
000145058 260__ $$aHoboken, NJ$$bWiley$$c2020
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000145058 520__ $$aThe 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.
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000145058 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000145058 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000145058 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000145058 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: genetics
000145058 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: metabolism
000145058 650_2 $$2MeSH$$aAnimals
000145058 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: genetics
000145058 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: metabolism
000145058 650_2 $$2MeSH$$aBrain: metabolism
000145058 650_2 $$2MeSH$$aBrain: pathology
000145058 650_2 $$2MeSH$$aMice
000145058 650_2 $$2MeSH$$aMice, Knockout
000145058 650_2 $$2MeSH$$aNeural Cell Adhesion Molecules: genetics
000145058 650_2 $$2MeSH$$aNeural Cell Adhesion Molecules: metabolism
000145058 650_2 $$2MeSH$$aProteomics
000145058 7001_ $$0P:(DE-2719)2812053$$aKlotz, Jakob$$b1$$udzne
000145058 7001_ $$0P:(DE-2719)9000408$$aDislich, Bastian$$b2$$udzne
000145058 7001_ $$0P:(DE-HGF)0$$aWanngren, Johanna$$b3
000145058 7001_ $$0P:(DE-2719)2812458$$aShmueli, Merav$$b4$$udzne
000145058 7001_ $$0P:(DE-2719)2810923$$aHerber, Julia$$b5$$udzne
000145058 7001_ $$0P:(DE-HGF)0$$aKuhn, Peer-Hendrik$$b6
000145058 7001_ $$0P:(DE-2719)2811530$$aKumar, Rohit$$b7$$udzne
000145058 7001_ $$0P:(DE-2719)2810825$$aKoeglsperger, Thomas$$b8$$udzne
000145058 7001_ $$0P:(DE-HGF)0$$aConrad, Marcus$$b9
000145058 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b10$$udzne
000145058 7001_ $$0P:(DE-2719)2812867$$aFeederle, Regina$$b11$$udzne
000145058 7001_ $$0P:(DE-HGF)0$$aVlachos, Andreas$$b12
000145058 7001_ $$0P:(DE-HGF)0$$aMichalakis, Stylianos$$b13
000145058 7001_ $$0P:(DE-HGF)0$$aJedlicka, Peter$$b14
000145058 7001_ $$0P:(DE-2719)2810938$$aMüller, Stephan A$$b15$$udzne
000145058 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F$$b16$$eLast author$$udzne
000145058 77318 $$2Crossref$$3journal-article$$a10.1096/fj.201902347r$$b : Wiley, 2019-12-27$$n2$$p2465-2482$$tThe FASEB Journal$$v34$$x0892-6638$$y2019
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000145058 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.3233/JAD-2011-101065$$o10.3233/JAD-2011-101065
000145058 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.3390/cells8030209$$o10.3390/cells8030209
000145058 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1074/mcp.RA118.000608$$o10.1074/mcp.RA118.000608
000145058 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.schres.2010.11.002$$o10.1016/j.schres.2010.11.002
000145058 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1002/ajmg.b.30726$$o10.1002/ajmg.b.30726