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論文
- タイトル
- α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes
- タイトル（英）
- α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes
- 参照URL
- https://researchmap.jp/masatohasegawa/published_papers/33625790
- 著者
- 著者（英）
- 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
- 担当区分
- 概要
- 概要（英）
- 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.
- 出版者・発行元
- 出版者・発行元（英）
- Public Library of Science (PLoS)
- 誌名
- 誌名（英）
- PLOS Biology
- 巻
- 19
- 号
- 7
- 開始ページ
- e3001287
- 終了ページ
- e3001287
- 出版年月
- 2021年7月20日
- 査読の有無
- 査読有り
- 招待の有無
- 掲載種別
- 研究論文（学術雑誌）
- ISSN
- DOI URL
- https://doi.org/10.1371/journal.pbio.3001287
- 共同研究・競争的資金等の研究課題
研究者
Hasegawa Masato
( )
,
野中 隆
(ノナカ タカシ)