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

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

Automated summary

This research indicates that α-syn fibrils affect the morphology and function of lysosomes in neuronal cells, facilitating their transmission to recipient cells through tunneling nanotubes. Lysosomes play a crucial role in the seeding and propagation of disease pathology by acting as a Trojan horse, as revealed by super-resolution and electron microscopy.