title: Synaptic autoregulation by metalloproteases and γ-secretase.
abstract: The proteolytic machinery comprising metalloproteases and γ-secretase, an intramembrane aspartyl protease involved in Alzheimer's disease, cleaves several substrates in addition to the extensively studied amyloid precursor protein. Some of these substrates, such as N-cadherin, are synaptic proteins involved in synapse remodeling and maintenance. Here we show, in rats and mice, that metalloproteases and γ-secretase are physiologic regulators of synapses. Both proteases are synaptic, with γ-secretase tethered at the synapse by δ-catenin, a synaptic scaffolding protein that also binds to N-cadherin and, through scaffolds, to AMPA receptor and a metalloprotease. Activity-dependent proteolysis by metalloproteases and γ-secretase takes place at both sides of the synapse, with the metalloprotease cleavage being NMDA receptor-dependent. This proteolysis decreases levels of synaptic proteins and diminishes synaptic transmission. Our results suggest that activity-dependent substrate cleavage by synaptic metalloproteases and γ-secretase modifies synaptic transmission, providing a novel form of synaptic autoregulation.
authors.affiliation: Department of Biochemistry, New York University Langone Medical Center, New York, New York 10016, USA. restis01@nyumc.org
authors.forename: Sophie
authors.initials: S
authors.lastname: Restituito
authors.forename: Latika
authors.initials: L
authors.lastname: Khatri
authors.forename: Ipe
authors.initials: I
authors.lastname: Ninan
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Weinberg
authors.forename: Edward B
authors.initials: EB
authors.lastname: Ziff
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D000818:Animals; D051177:Catenins / Q000172:deficiency / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D006624:Hippocampus / Q000201:enzymology*; D006706:Homeostasis / Q000502:physiology*; D008297:Male; D045726:Metalloproteases / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000201:enzymology*; D013570:Synaptic Membranes / Q000201:enzymology / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology*; D000095002:Delta Catenin
chemical_list: D051177:Catenins; D053829:Amyloid Precursor Protein Secretases; D045726:Metalloproteases; D000095002:Delta Catenin