Program in Cellular Neuroscience, Neurodegeneration and Repair, Departments of Neuroscience and of Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
Instituto de Neurobiología José del Castillo, Recinto de Ciencias Médicas, Universidad de Puerto Rico, San Juan, Puerto Rico.
Autophagy. 2022 Jul;18(7):1746-1747. doi: 10.1080/15548627.2022.2049151. Epub 2022 Mar 29.
Macroautophagy/autophagy occurs preferentially at synapses and responds to increased neuronal activity states. How synaptic autophagy is coupled to the neuronal activity state is largely unknown. Through genetic approaches we find that ATG-9, the only transmembrane protein in the core autophagy pathway, is transported from the -Golgi network to synapses in via the AP-3 complex. At synapses ATG-9 undergoes exo-endocytosis in an activity-dependent manner. Mutations that disrupt the endocytosis pathway, including a mutation associated with early onset Parkinsonism (EOP), lead to abnormal ATG-9 accumulation into subsynaptic clathrin-rich foci, and defects in activity-induced synaptic autophagy. We propose that ATG-9 exo-endocytosis links the activity-dependent synaptic vesicle cycle with autophagosome formation at synapses.
自噬作用（Macroautophagy/autophagy）优先发生在突触处，并对神经元活动状态的增加做出响应。然而，突触自噬作用如何与神经元活动状态偶联在很大程度上仍是未知的。通过遗传方法，我们发现 ATG-9 是核心自噬途径中唯一的跨膜蛋白，它通过 AP-3 复合物从 -高尔基体网络运输到突触处的内体（via the AP-3 complex）。在突触处，ATG-9 以活性依赖性方式经历外排-内吞作用（exo-endocytosis）。破坏内吞作用途径的突变，包括与早发性帕金森病（EOP）相关的突变，会导致异常的 ATG-9 积累到亚突触网格蛋白丰富的焦点中，并导致活性诱导的突触自噬作用缺陷。我们提出，ATG-9 的外排-内吞作用将活性依赖性突触囊泡循环与突触处的自噬体形成联系起来。
