Neurons Specialize in Presynaptic Autophagy: A Perspective to Ameliorate Neurodegeneration

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.