?-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

The accumulation of ?-synuclein (?-syn) aggregates in specific brain regions is a hallmark synucleinopathies including Parkinson disease (PD). ?-Syn propagate “prion-like” manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how participate the spreading ?-syn unclear. Here, by using super-resolution (SR) electron microscopy (EM), we find that fibrils affect morphology impair their function neuronal cells. In addition, demonstrate induce peripheral redistribution lysosomes, likely mediated transcription factor EB (TFEB), increasing efficiency fibrils’ transfer neighboring We also show lysosomal membrane permeabilization (LMP) allows seeding soluble have taken up from culture medium, and, more importantly, healthy coculture, following lysosome-mediated fibrils. Moreover, occurs mainly at both donor acceptor cells, after uptake medium transfer, respectively. Finally, heterotypic coculture system, determine origin nature between bearing damaged while receiving them. These findings thus contribute elucidation mechanism which spread TNTs, revealing crucial role working as Trojan horse for propagation pathology.