Format

Send to

Choose Destination
Elife. 2016 Jan 23;5. pii: e12748. doi: 10.7554/eLife.12748.

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

Author information

1
Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
2
Institut für Pathologie und Pathologische Anatomie, Technische Universität München, Munich, Germany.
3
Institute for Advanced Study, Technische Universität München, Munich, Germany.
4
Deutsches Zentrum für Neurodegenerative Erkrankungen, Munich, Germany.
5
Department of Animal Science, Institute for Animal Physiology, Ludwig-Maximilians-Universität München, Munich, Germany.
6
Institute of Pharmacology and Toxicology, Uniklinik RWTH Aachen, Aachen, Germany.
7
Institute of Biochemistry, Christian-Albrechts Universität zu Kiel, Kiel, Germany.
8
Karlsruhe Institute of Technology, Karlsruhe, Germany.
9
German Research Center for Environmental Health, Institute of Molecular Tumor immunology, Helmholtz Zentrum München, Munich, Germany.
10
Neurogenetics, Leibniz Institute for Neurobiology, Magdeburg, Germany.
11
Department of Functional Genomics, Institute for Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
12
Service-Gruppe für Elektronenmikroskopie, Zentrum für Molekulare Neurobiologie, Hamburg, Germany.
13
Munich Cluster for Systems Neurology, Munich, Germany.

Abstract

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.

KEYWORDS:

<i>e. coli</i>; ADAM; alzheimer; bioorthogonal chemistry; cell biology; human; mass spectrometry; metalloproteases; mouse; neuroscience; rat

PMID:
26802628
PMCID:
PMC4786429
DOI:
10.7554/eLife.12748
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center