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.
Highlights
Proteolysis of cell surface membrane proteins is a basic cellular mechanism that controls intercellular communication and the interaction of cells with their extracellular environment
We focused on a-disintegrin-andmetalloprotease 10 (ADAM10) substrate candidates, where antibodies were available to detect the reduction of the shed ectodomain in the conditioned medium of ADAM10-/- neurons as this allowed a quantitative comparison to the proteomic secretome protein identification with click sugars’ (SPECS) analysis
We investigated ectodomain cleavage and cellular levels of 11 substrates (CHL1, L1, CNTN2, NLGN1, NgCAM-related cell adhesion molecule (NRCAM), Low density lipoprotein receptor (LDLR), CDH2, MT4MMP, SEZ6, amyloid precursor protein (APP), NEO1), which we selected according to their quantitative reduction in ectodomain shedding in the current ADAM10 and the previous BACE1 SPECS study (Kuhn et al, 2012)
Summary
Proteolysis of cell surface membrane proteins is a basic cellular mechanism that controls intercellular communication and the interaction of cells with their extracellular environment. Constitutive ADAM10-deficient mice die at embryonic day 9.5 most likely due to a loss of Notch signaling (Hartmann et al, 2002) Another major substrate of ADAM10 is the amyloid precursor protein (APP) for which ADAM10 acts as the constitutive alpha-secretase (Postina et al, 2004; Lammich et al, 1999; Kuhn et al, 2010; Jorissen et al, 2010) and possesses the ability to prevent the generation of the pathogenic Ab peptide in Alzheimer’s disease (AD) (Lammich et al, 1999; Kuhn et al, 2010). Whether such a therapeutic approach is safe, remains to be seen, in particular because relatively little is known about ADAM10 substrates in brain
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