α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes.
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...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-07-01
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| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3001287&type=printable |
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| author | Aysegul Dilsizoglu Senol Maura Samarani Sylvie Syan Carlos M Guardia Takashi Nonaka Nalan Liv Patricia Latour-Lambert Masato Hasegawa Judith Klumperman Juan S Bonifacino Chiara Zurzolo |
| author_facet | Aysegul Dilsizoglu Senol Maura Samarani Sylvie Syan Carlos M Guardia Takashi Nonaka Nalan Liv Patricia Latour-Lambert Masato Hasegawa Judith Klumperman Juan S Bonifacino Chiara Zurzolo |
| author_sort | Aysegul Dilsizoglu Senol |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8d3afd767fd24d5ca05e43b7ded91e8a |
| institution | Kabale University |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2021-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-8d3afd767fd24d5ca05e43b7ded91e8a2025-08-20T03:44:40ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852021-07-01197e300128710.1371/journal.pbio.3001287α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes.Aysegul Dilsizoglu SenolMaura SamaraniSylvie SyanCarlos M GuardiaTakashi NonakaNalan LivPatricia Latour-LambertMasato HasegawaJudith KlumpermanJuan S BonifacinoChiara ZurzoloThe 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.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3001287&type=printable |
| spellingShingle | Aysegul Dilsizoglu Senol Maura Samarani Sylvie Syan Carlos M Guardia Takashi Nonaka Nalan Liv Patricia Latour-Lambert Masato Hasegawa Judith Klumperman Juan S Bonifacino Chiara Zurzolo α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes. PLoS Biology |
| title | α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes. |
| title_full | α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes. |
| title_fullStr | α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes. |
| title_full_unstemmed | α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes. |
| title_short | α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes. |
| title_sort | α synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3001287&type=printable |
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