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Sophie Restituito"Gamma secretase: a synaptic function ? "

Abstract :

Familial cases of AD (FAD) result from mutations in APP and presenilin 1 and 2 (PS1 and 2) proteins
. PS are thought to be the catalytic subunit of gamma secretase, and thus function in the generation of amyloid peptide from APP. However, the gamma secretase also cleaves other type I transmembrane proteins, including Notch, Cadherin and ErbB4. Other binding partners of PS1 have also been identified. One of these, NPRAP (delta catenin), has been shown to interact with ABP (AMPA receptor binding protein), by our lab. Thus, the secretase could have a more ubiquitous function in degrading proteins than initially thought. We therefore asked if gamma secretase is present and active at synapses and if it plays a role in modifying synaptic architecture and function through the cleavage of cadherins, which are synaptic cell adhesion molecules. We find by immunocytochemistry that PS1 and nicastrin, two gamma secretase components, are present at synapses of hippocampal neurons in culture and colocalize with gamma secretase substrates, including cadherin and ErbB4, and with other synaptic proteins, including AMPA receptors. Synaptic localization was confirmed by subcellular fractionation. Furthermore, we find that gamma secretase can be active at synapses, as indicated by cadherin cleavage in synaptosomes. These data suggest that gamma secretase is synaptic and thus may modify synaptic architecture and function through cleavage of synaptic substrates. A deregulation of this protease, such as by FAD mutation, could pathologically activate secretase function at synapses, leading to synapse degradation and loss.  

Selected publications

Restituito S, Couve A, Bawagan H, Jourdain S, Pangalos MN, Calver AR, Freeman KB, Moss SJ.
Multiple motifs regulate the trafficking of GABA(B) receptors at distinct checkpoints within the secretory pathway.
Mol Cell Neurosci. 2005 Apr;28(4):747-56.
Thuault S J, Brown JT. Sheardown SA,Jourdain S, Fairfax B, Spencer JP, Restituito S, Nation JHL, Topps S, Medhurst AD, Randall AD, Couve A, Moss SJ, Collingridge GL, Pangalos MN, Davies CH and Calver AR (2004); The GABAB2 subunit is critical for the trafficking and function of native GABAB receptors. Biochem Pharmacol. (2004) 68 (8): 1655-66.
Couve A, Restituito S, Brandon JM, Charles KJ, Bawagan H, Freeman KB, Pangalos MN, Calver AR & Moss SJ. (2004): Marlin-1, a novel RNA-binding protein associates with GABA receptors. J Biol Chem. 279: 13934-43
Rousset M, Cens T, Restituito S, Barrere C, Black JLIII, McEnery M & Charnet P (2001): functional roles of gamma 2, gamma 3 and gamma 4; three new Ca channel subunits, on P/Q type Ca channels expressed in Xenopus laevi oocytes. J Physiol. 532 (Pt 3): 583-93.

Agnès Hémar