In:
PLOS Biology, Public Library of Science (PLoS), Vol. 19, No. 7 ( 2021-7-20), p. e3001287-
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001287
DOI:
10.1371/journal.pbio.3001287.g001
DOI:
10.1371/journal.pbio.3001287.g002
DOI:
10.1371/journal.pbio.3001287.g003
DOI:
10.1371/journal.pbio.3001287.g004
DOI:
10.1371/journal.pbio.3001287.g005
DOI:
10.1371/journal.pbio.3001287.g006
DOI:
10.1371/journal.pbio.3001287.g007
DOI:
10.1371/journal.pbio.3001287.g008
DOI:
10.1371/journal.pbio.3001287.g009
DOI:
10.1371/journal.pbio.3001287.g010
DOI:
10.1371/journal.pbio.3001287.g011
DOI:
10.1371/journal.pbio.3001287.s001
DOI:
10.1371/journal.pbio.3001287.s002
DOI:
10.1371/journal.pbio.3001287.s003
DOI:
10.1371/journal.pbio.3001287.s004
DOI:
10.1371/journal.pbio.3001287.s005
DOI:
10.1371/journal.pbio.3001287.s006
DOI:
10.1371/journal.pbio.3001287.s007
DOI:
10.1371/journal.pbio.3001287.s008
DOI:
10.1371/journal.pbio.3001287.s009
DOI:
10.1371/journal.pbio.3001287.s010
DOI:
10.1371/journal.pbio.3001287.s011
DOI:
10.1371/journal.pbio.3001287.s012
DOI:
10.1371/journal.pbio.3001287.s013
DOI:
10.1371/journal.pbio.3001287.r001
DOI:
10.1371/journal.pbio.3001287.r002
DOI:
10.1371/journal.pbio.3001287.r003
DOI:
10.1371/journal.pbio.3001287.r004
DOI:
10.1371/journal.pbio.3001287.r005
DOI:
10.1371/journal.pbio.3001287.r006
Sprache:
Englisch
Verlag:
Public Library of Science (PLoS)
Publikationsdatum:
2021
ZDB Id:
2126773-X
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