Molecular mechanism and function of neuronal ER-phagy

神经元内质网自噬的分子机制和功能

• 批准号: 466163467
• 负责人: Professor Volker Haucke, Ph.D.
• 金额: --
• 依托单位: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/466163467?language=en
• 关键词: Molecular; mechanism; function; neuronal; ER

Within neuronal networks, electrical signals and chemical neurotransmitters allow for rapid communication from the presynaptic compartment of one neuron to a postsynaptic compartment of another neuron. To support neuronal and synaptic integrity, neurons have evolved strategies for maintaining proper proteostasis and removing damaged proteins. Autophagy is a process in which parts of the cytoplasm are engulfed by membrane and sent for degradation. Work from us and others have not only demonstrated that autophagy is important for neuronal function but also revealed novel molecular links between the machineries for synaptic vesicle (SV) recycling and the autophagy system. However, which neuronal substrates are turned over via the autophagy-lysosomal pathway, how this pathway is controlled and how it is linked to neuronal activity is incompletely understood. To address these crucial questions, we generated knockout mice conditionally lacking the essential autophagy protein ATG5. We discovered that loss of neuronal autophagy causes the selective accumulation of tubular Endoplasmic Reticulum (ER) in axons under physiological conditions, resulting in increased excitatory neurotransmission as a consequence of elevated calcium release from ER stores via ryanodine receptors. We therefore hypothesize that neuronal autophagy controls axonal ER calcium stores to regulate neurotransmission in healthy neurons and in the brain. The overall objective of the proposed project is to understand which specific adaptors control the ER-phagy (i.e. ER degradation by autophagy) process in central nervous system neurons (WP1), how neuronal ER-phagy is regulated by neuronal activity or other stimuli (WP2), and what the physiological roles of ER-phagy are in the post- versus the presynaptic compartment (WP3).

在神经元网络内，电信号和化学神经递质允许从一个神经元的突触前区室到另一个神经元的突触后区室的快速通信。为了支持神经元和突触的完整性，神经元已经进化出维持适当的蛋白质稳态和去除受损蛋白质的策略。自噬是细胞质的一部分被膜吞噬并降解的过程。我们和其他人的工作不仅证明了自噬对神经元功能很重要，而且还揭示了突触囊泡（SV）回收机制与自噬系统之间的新分子联系。然而，哪些神经元底物通过自噬-溶酶体途径被翻转，该途径如何被控制以及它如何与神经元活性相关联还不完全清楚。为了解决这些关键问题，我们产生了条件性缺乏必需的自噬蛋白ATG 5的敲除小鼠。我们发现，神经元自噬的丧失导致在生理条件下轴突中的管状内质网（ER）的选择性积累，导致兴奋性神经传递增加，这是由于通过兰尼碱受体从ER储存中释放的钙升高的结果。因此，我们假设神经元自噬控制轴突ER钙储存，以调节健康神经元和大脑中的神经传递。该拟议项目的总体目标是了解哪些特定的衔接子控制中枢神经系统神经元（WP 1）中的ER吞噬（即自噬引起的ER降解）过程，神经元ER吞噬如何受到神经元活动或其他刺激的调节（WP 2），以及ER吞噬在突触后区室和突触前区室中的生理作用（WP 3）。