SAP97-mediated ADAM10 trafficking from Golgi outposts depends on PKC phosphorylation.

Claudia Saraceno (1) , Elena Marcello (1) , Daniele Di Marino (2) , Barbara Borroni (3) , Sylvie Claeysen (4) , Julie Perroy (4) , Alessandro Padovani (3) , Anna Tramontano (5, 2) , Fabrizio Gardoni (1) , Monica Di Luca (1)

1 Department of Pharmacological Sciences and Biomolecular
2 Dipartimento di Fisica [Roma La Sapienza]
3 University of Brescia
4 IGF - Institut de Génomique Fonctionnelle
5 Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti

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.

Domains: Biochemistry, Molecular Biology; Cellular Biology

Claudia Saraceno, Elena Marcello, Daniele Di Marino, Barbara Borroni, Sylvie Claeysen, et al.. SAP97-mediated ADAM10 trafficking from Golgi outposts depends on PKC phosphorylation.. Cell Death and Disease, 2014, 5, pp.e1547. ⟨10.1038/cddis.2014.492⟩. ⟨pasteur-01203115⟩