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

Aysegul Dilsizoglu Senol (1) , Maura Samarani (1) , Sylvie Syan (1) , Carlos M. Guardia (2) , Takashi Nonaka (3) , Nalan Liv (4) , Patricia Latour-Lambert (5) , Masato Hasegawa (3) , Judith Klumperman (4) , Juan S Bonifacino (6) , Chiara Zurzolo (1)

1 Trafic membranaire et Pathogénèse
2 NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development
3 TMIMS - Tokyo Metropolitan Institute of Medical Science
4 University Medical Center [Utrecht]
5 Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions
6 NIH - National Institutes of Health [Bethesda, MD, USA]

The accumulation of α-synuclein aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson’s disease. α-Synuclein 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 α-synuclein aggregates is unclear. Here, by using super-resolution and electron microscopy, we find that α-synuclein fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-synuclein fibrils induce peripheral redistribution of lysosomes, likely mediated by TFEB, increasing the efficiency of α-synuclein fibrils’ transfer to neighboring cells. We also show that lysosomal membrane permeabilization allows the seeding of soluble α-synuclein in cells that have taken up α-synuclein fibrils from the culture medium and, more importantly, in healthy cells in co-culture, 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 α-syn fibrils from the medium and following their transfer, respectively. Finally, by using a heterotypic co-culture system, we determine the origin and nature of the lysosomes transferred between cells and we show that donor cells bearing α-synuclein 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 α-synuclein 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.

Domaines: Biochimie, Biologie Moléculaire

Aysegul Dilsizoglu Senol, Maura Samarani, Sylvie Syan, Carlos M. Guardia, Takashi Nonaka, et al.. α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes. PLoS Biology, 2021, 19 (7), pp.e3001287. ⟨10.1371/journal.pbio.3001287⟩. ⟨pasteur-03274582⟩