VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
VIB Center for Brain & Disease Research, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium; KU Leuven, Department for Human Genetics, Leuven Institute for Neurodegenerative Disease, 3000 Leuven, Belgium.
Neuron. 2016 Nov 23;92(4):829-844. doi: 10.1016/j.neuron.2016.09.037. Epub 2016 Oct 6.
Synapses are often far from the soma and independently cope with proteopathic stress induced by intense neuronal activity. However, how presynaptic compartments turn over proteins is poorly understood. We show that the synapse-enriched protein EndophilinA, thus far studied for its role in endocytosis, induces macroautophagy at presynaptic terminals. We find that EndophilinA executes this unexpected function at least partly independent of its role in synaptic vesicle endocytosis. EndophilinA-induced macroautophagy is activated when the kinase LRRK2 phosphorylates the EndophilinA-BAR domain and is blocked in animals where EndophilinA cannot be phosphorylated. EndophilinA-phosphorylation promotes the formation of highly curved membranes, and reconstitution experiments show these curved membranes serve as docking stations for autophagic factors, including Atg3. Functionally, deregulation of the EndophilinA phosphorylation state accelerates activity-induced neurodegeneration. Given that EndophilinA is connected to at least three Parkinson's disease genes (LRRK2, Parkin and Synaptojanin), dysfunction of EndophilinA-dependent synaptic macroautophagy may be common in this disorder.
突触通常远离神经元胞体，并且可以独立应对由强烈神经元活动引起的蛋白病变应激。然而，人们对突触前区如何翻转蛋白质知之甚少。我们发现富含突触的蛋白内收蛋白 A（EndophilinA），迄今为止因其在胞吞作用中的作用而被研究，在突触前末端诱导巨自噬。我们发现 EndophilinA 至少部分独立于其在突触囊泡胞吞作用中的作用执行此意外功能。当激酶 LRRK2 磷酸化 EndophilinA-BAR 结构域时，EndophilinA 诱导的巨自噬被激活，并且在不能磷酸化 EndophilinA 的动物中被阻断。EndophilinA 磷酸化促进高度弯曲的膜的形成，并且重建实验表明这些弯曲的膜充当自噬因子的停靠站，包括 Atg3。功能上，EndophilinA 磷酸化状态的失调加速了活性诱导的神经退行性变。鉴于 EndophilinA 与至少三个帕金森病基因（LRRK2、Parkin 和 Synaptojanin）相关，依赖于 EndophilinA 的突触巨自噬功能障碍在这种疾病中可能很常见。
