Differential alpha-Synuclein-induced Autophagy Dysfunction in Neuronal and Microglial Cells drives Tunneling Nanotubes and Aggregate Spread to Microglia

Tunneling nanotubes (TNTs) represent a major form of intercellular communication, enabling material exchange of different kinds over long distances between the connected cells. Previous investigations have demonstrated the efficient directional transfer of alpha-Synuclein (alpha-Syn) aggregates from neuronal cells to microglia. However, the mechanisms underlying this directional specificity have remained elusive. Here, we investigate the localization, dynamics, and impacts of alpha-Syn aggregates on the lysosome and autophagic pathways in neuronal and microglial cells. Our findings reveal differential localization of aggregates with lysosomes of neuronal and microglial cells alongside a disparity in lysosomal dynamics. Microglia exhibit a high propensity for lysosomal turnover, particularly through lysophagy, while neuronal lysosomes display compromised degradative capacity and impaired autophagic flux. Consequently, aggregates in neuronal cells are less efficiently targeted for degradation. Furthermore, perturbation of autophagy in neuronal cells elevates TNT-mediated aggregate transfer to microglia. Thus, while revealing distinct effects of alpha-Syn aggregates in neuronal and microglial cells, our study identifies dysfunctional autophagy as a pivotal determinant driving the preferential directional transfer of aggregates from neurons to microglia.