OSBP Participates in Neural Damage Repair by Regulating Lysosome Transport Under Oxidative Stress

Oxidative stress is a major pathological factor in acute brain injury, such as traumatic brain injury (TBI). As highly branched cells, the transport of lysosomes plays a crucial role in neuronal homeostasis. However, the effects and mechanisms of oxidative damage on axonal lysosome transport remain unknown. In this study, we demonstrated that the downregulation of the membrane lipid orchestrator oxysterol-binding protein (OSBP) induced by oxidative stress alters the subcellular distribution of lysosomes in neurons through regulating lysosomal phosphatidylinositol-4-monophosphate (PI(4)P)/phosphatidylinositol-3-monophosphate (PI(3)P) contents, thus disrupting lysosomal transport. The results of the cell experiments confirmed the occurrence of an autophagic pressure burst, disordered anterograde lysosome transport, and an imbalance in the PI(4)P/PI(3)P ratio in neurons after H₂O₂ treatment. Mechanistically, oxidative damage reduced neuronal OSBP protein levels, thus contributing to lysosomal PI(4)P storage. Furthermore, a protein‒liposome binding assay revealed that compared with liposomes containing PI(4)P, liposomes containing PI(3)P or cholesterol presented decreased coprecipitation of Arl8. The overexpression of OSBP restored the PI(4)P/PI(3)P content, improved the binding ability of Arl8 to bind to lysosomes, increased lysosome localization in neurites, and promoted axonal injury repair. Finally, overexpression of neuronal OSBP through adeno-associated virus intervention in vivo alleviated dendritic damage and improved the neurological function of mice with TBI. Taken together, these findings suggest that disturbance of OSBP induced by oxidative stress results in abnormal lysosomal distribution and contributes to neuronal malfunction in TBI, and OSBP could be a potential target to promote neuronal repair and regeneration by regulating lysosomal lipid composition and axonal localization.