Abstract: Oligodendrocyte precursor cells (OPCs) tile the central nervous system ubiquitously, accounting for about 5% of the total cell population in the central nervous system. Beyond their role in myelination, OPCs actively shape neural circuits (Fang and Bai, 2023), by releasing neuromodulators, pruning synapses, maintaining the homeostasis of extracellular potassium concentration, and interacting with endothelial cells. These cells feature a small cell body with highly branched processes, enabling communication with neighboring cells. OPCs establish contacts at various sites of neurons, including synaptic connections with axons and direct physical interactions at the nodes of Ranvier and neuronal somata. Recently, Fang et al. (2025) identified a contact-dependent signaling mechanism between OPCs and neurons. This interaction was observed universally across brain gray matter, with 91%–99% of neurons contacted by OPC processes, a phenomenon also confirmed in human cortical neurons. Functional studies revealed that OPCneuron contact promotes lysosomal exocytosis from neurons. Notably, when OPC processes were diminished, either by genetic ablation of L-type voltage-gated calcium channels in OPCs or acute OPC depletion via induced diphtheria toxin A expression, the frequency of neuron-OPC contacts decreased. Consequently, affected neurons exhibited aberrant accumulation of enlarged lysosomes and lipid droplet in the somata (indicating lysosomal dysfunction), as well as molecular hallmarks of neuronal senescence and neurodegeneration. Many studies have established that impaired lysosomal function and exocytosis are strongly associated with neurodegenerative diseases and cellular senescence (Samie and Xu, 2014; Stagi et al., 2014; Lee et al., 2022; Xie et al., 2022; Figure 1). Lysosomes function as the waste disposal and recycling system of a cell, degrading biomolecules, damaged organelles, and foreign particles such as bacteria or viruses. These degraded materials are expelled from the cell via lysosomal exocytosis, a process in which lysosomes traffic to the plasma membrane, fuse with it, and release their contents. This mechanism is critical for clearing neurotoxic aggregates, thereby protecting cells from damage and death. Thus, the control of neuronal lysosomal exocytosis and function by OPC may serve as a novel therapeutic target for neurodegenerative diseases.