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

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.DOI: http://dx.doi.org/10.7554/eLife.12748.001

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

“…This indicated MMP and ADAM family proteases as candidate enzymes, a prediction consistent with the reported enzyme(s) responsible for Nlgn1 cleavage 17,18 and neural ADAM10 targets 19 . Active slice CM generated in the absence and presence of various protease inhibitors exhibited decreased neuroligin-3 shedding with MMP9 and ADAM10 inhibitors (Fig.…”

“…4g). ADAM10 mediates cleavage of numerous cell surface proteins, prominently targeting synapse-associated proteins 19 , and also plays an important role in amyloid protein processing 27 . While ADAM10 inhibition appears well-tolerated in clinical trials 25,26 , and caused no overt neurotoxicity here (Extended Data Fig.…”

Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage

“…However, we reckon that more detailed analysis is required to understand the molecular mechanism of activity-dependent NLGNs shedding at the synapse and its consequences for synaptic functions. To date, two specific secretory proteases were proposed to cleave NLGN1: matrix metalloproteinase 9 (MMP-9) [52] and disintegrin and metalloproteinase domain-containing protein 10 (ADAM-10) [53,[69][70][71]. Recently, the cleaved NLGN3 was detected in the medium from optogenetically stimulated acute cortical slices WT Fmr1 KO Fig.…”

La chimie-click débusque les substrats d’ADAM10

“…Il définit un groupe de réactions chimiques quasi parfaites, modulables, simples à mettre en oeuvre et se produisant en absence de solvant. Si la plus connue est la réaction de cycloaddition azoture-alcyne catalysée par le cuivre (CuAAC), des approches sans cuivre ont été développées, notamment celles utilisant le DBCO (dibenzocyclooctyl) employé par Kuhn et al [4]. Ces réactions sont d'une grande sélectivité, permettant de coupler divers types de molécules fonctionnalisées sans interférer avec l'environnement biologique, et ont donc trouvé de nombreuses applications en biologie.…”

“…Lorsque le gène codant ADAM10 est invalidé spécifiquement dans les neurones après la naissance, les souris présentent des épisodes d'épilepsie, des déficits d'apprentissage et des altérations des structures postsynaptiques [3]. Cependant, les substrats connus d'ADAM10 n'expliquent qu'en partie ces phénotypes, incitant Kuhn et ses collègues à chercher d'autres substrats d'ADAM10 dans le système nerveux central [4].…”