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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, Herber, Julia, Ludwig, Andreas, Kremmer, Elisabeth, Montag, Dirk, Müller, Ulrike, Schweizer, Michaela, Saftig, Paul, Bräse, Stefan, Lichtenthaler, Stefan F·2016·eLife
DOI 10.7554/elife.12748PMC PMC4786429
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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.

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Crossref · 10.7554/elife.12748

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  • APLP2 is cleaved to about 60% by BACE1 and to 40% by ADAM10 in neurons, but the percentages may strongly vary for each substrate.

    “For example, the APP homolog APLP2 is cleaved to about 60 % by BACE1 and to 40 % by ADAM10 in neurons, but the percentages may strongly vary for each substrate [38].”

    From Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons (2016) · cites this paper as [38]

    The Results section (‘Cross-talk between ADAM10 and BACE1’; page unavailable) reports that the contribution of the two proteases differs among neuronal substrates, supporting the claim's general qualification. But APLP2 is not among the substrates listed there, and no passage found gives the claimed 60% BACE1/40% ADAM10 split for APLP2. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Surface levels of the LDL receptor (LDLR) were not altered upon BACE inhibition.

    “As a control, surface levels of the LDL-receptor (LDLR), which is a substrate of ADAM10, but not of BACE1 [38], were not altered upon BACE inhibition.”

    From Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons (2016) · cites this paper as [38]

  • Several other previously identified BACE1 substrates, such as CHL1, L1, contactin-2, APP and its homolog APLP2, are not exclusively cleaved by BACE1, but also by other proteases, including ADAM10.

    “Several other previously identified BACE1 substrates, such as CHL1, L1, contactin-2, APP and its homolog APLP2, are not exclusively cleaved by BACE1, but also by other proteases, including ADAM10 [15, 38].”

    From Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons (2016) · cites this paper as [38]

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Metadata

Authors
Kuhn, P.-H., Colombo, A. V., Schusser, B., Dreymueller, D., Wetzel, S., Schepers, U., Herber, J., Ludwig, A., Kremmer, E., Montag, D., Müller, U., Schweizer, M., Saftig, P., Bräse, S., & Lichtenthaler, S. F.
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2016-01-23
Volume
5
ISSN
2050-084X
DOI
10.7554/elife.12748
PMC
PMC4786429
Cited by
163
References
5
Language
en
Licence
Funders
  • Deutsche Forschungsgemeinschaft
  • Breuer Foundation
  • Stiftung VERUM
  • Technische Universitaet Muenchen, Institute for Advanced Study

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