Mishra Abhishek Kumar, Tripathi Manish Kumar, Kumar Dipak, Gupta Satya Prakash
Department of Zoology, Government Shaheed Gendsingh College, Charama, Uttar Bastar Kanker, 494 337, Chhattisgarh, India.
School of Pharmacy, Faculty of Medicine, Institute for Drug Research, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel.
Mol Neurobiol. 2025 Feb;62(2):2626-2640. doi: 10.1007/s12035-024-04399-8. Epub 2024 Aug 14.
The efficient and prolonged neurotransmission is reliant on the coordinated action of numerous synaptic proteins in the presynaptic compartment that remodels synaptic vesicles for neurotransmitter packaging and facilitates their exocytosis. Once a cycle of neurotransmission is completed, membranes and associated proteins are endocytosed into the cytoplasm for recycling or degradation. Both exocytosis and endocytosis are closely regulated in a timely and spatially constrained manner. Recent research demonstrated the impact of dysfunctional synaptic vesicle retrieval in causing retrograde degeneration of midbrain neurons and has highlighted the importance of such endocytic proteins, including auxilin, synaptojanin1 (SJ1), and endophilin A (EndoA) in neurodegenerative diseases. Additionally, the role of other associated proteins, including leucine-rich repeat kinase 2 (LRRK2), adaptor proteins, and retromer proteins, is being investigated for their roles in regulating synaptic vesicle recycling. Research suggests that the degradation of defective vesicles via presynaptic autophagy, followed by their recycling, not only revitalizes them in the active zone but also contributes to strengthening synaptic plasticity. The presynaptic autophagy rejuvenating terminals and maintaining neuroplasticity is unique in autophagosome formation. It involves several synaptic proteins to support autophagosome construction in tiny compartments and their retrograde trafficking toward the cell bodies. Despite having a comprehensive understanding of ATG proteins in autophagy, we still lack a framework to explain how autophagy is triggered and potentiated in compact presynaptic compartments. Here, we reviewed synaptic proteins' involvement in forming presynaptic autophagosomes and in retrograde trafficking of terminal cargos. The review also discusses the status of endocytic proteins and endocytosis-regulating proteins in neurodegenerative diseases and strategies to combat neurodegeneration.
高效且持久的神经传递依赖于突触前区室中众多突触蛋白的协同作用，这些蛋白重塑突触小泡以进行神经递质包装并促进其胞吐作用。一旦神经传递周期完成，膜和相关蛋白就会被内吞到细胞质中进行再循环或降解。胞吐作用和内吞作用都以时间和空间受限的方式受到严格调控。最近的研究表明，功能失调的突触小泡回收会导致中脑神经元逆行性变性，并凸显了包括辅助蛋白、突触素1（SJ1）和内吞蛋白A（EndoA）等内吞蛋白在神经退行性疾病中的重要性。此外，其他相关蛋白的作用，包括富含亮氨酸重复激酶2（LRRK2）、衔接蛋白和逆转录酶蛋白，正在被研究其在调节突触小泡再循环中的作用。研究表明，通过突触前自噬降解有缺陷的小泡，然后进行再循环，不仅能使它们在活性区恢复活力，还有助于增强突触可塑性。突触前自噬使突触终末恢复活力并维持神经可塑性，这在自噬体形成过程中是独特的。它涉及多种突触蛋白，以支持在微小区室中构建自噬体及其向细胞体的逆行运输。尽管我们对自噬中的自噬相关蛋白（ATG）有了全面的了解，但我们仍然缺乏一个框架来解释自噬是如何在紧密的突触前区室中被触发和增强的。在这里，我们综述了突触蛋白在形成突触前自噬体和终末货物逆行运输中的作用。该综述还讨论了神经退行性疾病中内吞蛋白和内吞作用调节蛋白的状况以及对抗神经退行性变的策略。
