α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes
Year: 2021
Type: article
Abstract: The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson disease (PD). α-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 α-syn aggregates is unclear. Here, by using super-resolution (SR) and electron microscopy (EM), we find that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-syn fibrils induce peripheral redistribution of lysosomes, likely mediated by transcription factor EB (TFEB), increasing the efficiency of α-syn fibrils' transfer to neighboring cells. We also show that lysosomal membrane permeabilization (LMP) allows the seeding of soluble α-syn in cells that have taken up α-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 α-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 α-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 α-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.
Source: PLoS Biology
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,724
Funders: Japan Agency for Medical Research and Development, Brain Science Foundation, Fondation Vaincre Alzheimer, European Commission, Agence Nationale de la Recherche, ZonMw, Fondation pour la Recherche Médicale, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Institut Pasteur, Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone, Royal De Heus, National Institutes of Health, Horizon 2020 Framework Programme, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Core Research for Evolutional Science and Technology
Awards: G120131529, G1665659508, TDP-43のシナプス伝播を介した病態解明, G2576085165, Tunneling Nanotubes: structure/function characterization and role in prion-like spreading of neurodegenerative diseases, G2905285681, G3000700502, G3264461099, G3345895242, Protein Trafficking In The Endosomal-Lysosomal System, G5420063140, G6113488458, G6468888895, G6709574028, G7240651115, G743503607, G7730087503, Understanding the role of lysosomes in the intercellular TNT-mediated spreading of α-synuclein and the impact of lysosomal dysfunction, G8172133935, Développment d'une infrastructure française distribuée coordonnée, G8910198989, Protein Trafficking In The Endosomal-Lysosomal System
OpenAlex ID: W3186717564