Tunneling nanotubes spread fibrillar α‐synuclein by intercellular trafficking of lysosomes

Abstract Synucleinopathies such as Parkinson's disease are characterized by the pathological deposition of misfolded α‐synuclein aggregates into inclusions throughout the central and peripheral nervous system. Mounting evidence suggests that intercellular propagation of α‐synuclein aggregates may contribute to the neuropathology; however, the mechanism by which spread occurs is not fully understood. By using quantitative fluorescence microscopy with co‐cultured neurons, here we show that α‐synuclein fibrils efficiently transfer from donor to acceptor cells through tunneling nanotubes ( TNT s) inside lysosomal vesicles. Following transfer through TNT s, α‐synuclein fibrils are able to seed soluble α‐synuclein aggregation in the cytosol of acceptor cells. We propose that donor cells overloaded with α‐synuclein aggregates in lysosomes dispose of this material by hijacking TNT ‐mediated intercellular trafficking. Our findings thus reveal a possible novel role of TNT s and lysosomes in the progression of synucleinopathies.