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Systematic substrate identification indicates a central role for the metalloprotease ADAM10 in axon targeting and synapse function

Kuhn, Peer-Hendrik; Colombo, Alessio Vittorio; Schusser, Benjamin; Dreymueller, Daniela; Wetzel, Sebastian; Schepers, Ute 1; Herber, Julia; Ludwig, Andreas; Kremmer, Elisabeth; Montag, Dirk; Müller, Ulrike; Schweizer, Michaels; Saftig, Paul; Bräses, Stefan 1; Lichtenthaler, Stefan F.
1 Karlsruher Institut für Technologie (KIT)

Abstract (englisch):

Metzincin metalloproteases have major roles in intercellular communication by modulating the function of membrane proteins. One of the proteases is the a-disintegrin-and-metalloprotease 10 (ADAM10) which acts as alpha-secretase of the Alzheimer's disease amyloid precursor protein. ADAM10 is also required for neuronal network functions in murine brain, but neuronal ADAM10 substrates are only partly known. With a proteomic analysis of Adam10-deficient neurons we identified 91, mostly novel ADAM10 substrate candidates, making ADAM10 a major protease for membrane proteins in the nervous system. Several novel substrates, including the neuronal cell adhesion protein NrCAM, are involved in brain development. Indeed, we detected mistargeted axons in the olfactory bulb of conditional ADAM10-/- mice, which correlate with reduced cleavage of NrCAM, NCAM and other ADAM10 substrates. In summary, the novel ADAM10 substrates provide a molecular basis for neuronal network dysfunctions in conditional ADAM10-/- mice and demonstrate a fundamental function of ADAM10 in the brain.


Volltext §
DOI: 10.5445/IR/1000057782
Originalveröffentlichung
DOI: 10.7554/eLife.12748
Scopus
Zitationen: 123
Web of Science
Zitationen: 121
Dimensions
Zitationen: 136
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Toxikologie und Genetik (ITG)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2016
Sprache Englisch
Identifikator ISSN: 2050-084X
urn:nbn:de:swb:90-577821
KITopen-ID: 1000057782
HGF-Programm 47.01.01 (POF III, LK 01) Biol.Netzwerke u.Synth.Regulat. ITG+ITC
Erschienen in eLife
Verlag eLife Sciences Publications
Band 5
Heft JANUARY2016
Seiten e12748
Vorab online veröffentlicht am 23.01.2016
Nachgewiesen in Dimensions
Web of Science
Scopus
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