Department of Biochemistry, New York University Langone Medical Center, New York, New York 10016, USA.
J Neurosci. 2011 Aug 24;31(34):12083-93. doi: 10.1523/JNEUROSCI.2513-11.2011.
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.
包含金属蛋白酶和 γ-分泌酶的蛋白水解酶复合物，作为一种参与阿尔茨海默病的跨膜天冬氨酸蛋白酶，除了广泛研究的淀粉样前体蛋白外，还能切割几种底物。这些底物中的一些，如 N-钙黏蛋白，是参与突触重塑和维持的突触蛋白。在这里，我们在大鼠和小鼠中表明，金属蛋白酶和 γ-分泌酶是突触的生理调节剂。这两种蛋白酶都是突触相关的，γ-分泌酶通过 δ-连环蛋白固定在突触上，δ-连环蛋白是一种突触支架蛋白，也与 N-钙黏蛋白结合，并通过支架与 AMPA 受体和一种金属蛋白酶结合。金属蛋白酶和 γ-分泌酶的活性依赖性蛋白水解作用发生在突触的两侧，其中金属蛋白酶的切割依赖于 NMDA 受体。这种蛋白水解作用降低了突触蛋白的水平，并减弱了突触传递。我们的结果表明，突触金属蛋白酶和 γ-分泌酶的活性依赖性底物切割改变了突触传递，为突触自身调节提供了一种新形式。
