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

Abstract : 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.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-03274582
Contributor : Reine Bouyssie Connect in order to contact the contributor
Submitted on : Wednesday, June 30, 2021 - 11:39:27 AM
Last modification on : Tuesday, October 19, 2021 - 10:29:31 PM
Long-term archiving on: : Friday, October 1, 2021 - 6:24:07 PM

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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, Public Library of Science, In press. ⟨pasteur-03274582⟩

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