title: SAP97-mediated ADAM10 trafficking from Golgi outposts depends on PKC phosphorylation.
abstract: A disintegrin and metalloproteinase 10 (ADAM10) is the major α-secretase that catalyzes the amyloid precursor protein (APP) ectodomain shedding in the brain and prevents amyloid formation. Its activity depends on correct intracellular trafficking and on synaptic membrane insertion. Here, we describe that in hippocampal neurons the synapse-associated protein-97 (SAP97), an excitatory synapse scaffolding element, governs ADAM10 trafficking from dendritic Golgi outposts to synaptic membranes. This process is mediated by a previously uncharacterized protein kinase C phosphosite in SAP97 SRC homology 3 domain that modulates SAP97 association with ADAM10. Such mechanism is essential for ADAM10 trafficking from the Golgi outposts to the synapse, but does not affect ADAM10 transport from the endoplasmic reticulum. Notably, this process is altered in Alzheimer's disease brains. These results help in understanding the mechanism responsible for the modulation of ADAM10 intracellular path, and can constitute an innovative therapeutic strategy to finely tune ADAM10 shedding activity towards APP.
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Saraceno
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Marcello
authors.affiliation: Department of Physics, Sapienza University of Rome, P.le A. Moro, 5-00187 Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Di Marino
authors.affiliation: Department of Neurological Sciences, University of Brescia, 25125 Brescia, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Borroni
authors.affiliation: 1] CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France [2] Inserm, U661, Montpellier, France [3] Universités de Montpellier 1 and 2, UMR-5203, Montpellier, France.
authors.forename: S
authors.initials: S
authors.lastname: Claeysen
authors.affiliation: 1] CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France [2] Inserm, U661, Montpellier, France [3] Universités de Montpellier 1 and 2, UMR-5203, Montpellier, France.
authors.forename: J
authors.initials: J
authors.lastname: Perroy
authors.affiliation: Department of Neurological Sciences, University of Brescia, 25125 Brescia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Padovani
authors.affiliation: 1] Department of Physics, Sapienza University of Rome, P.le A. Moro, 5-00187 Rome, Italy [2] Institute Pasteur Fondazione Cenci Bolognetti, Sapienza University of Rome, P.le A. Moro, 5-00187 Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Tramontano
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Gardoni
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Di Luca
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000378:metabolism*; D000072197:ADAM10 Protein; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000074288:Discs Large Homolog 1 Protein; D004789:Enzyme Activation; D006056:Golgi Apparatus / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D057907:Post-Synaptic Density / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D013569:Synapses / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D010769:Phosphothreonine; D011493:Protein Kinase C; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human