α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes.
α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes.
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α - 突触核蛋白原纤维破坏溶酶体的结构与功能，从而借助隧道纳米管在细胞间传播蛋白质错误折叠。
DOI：
10.1371/journal.pbio.3001287
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发表时间：
2021-07
期刊：
影响因子：
9.8
通讯作者：
Zurzolo C
中科院分区：
文献类型：
--
作者：
Dilsizoglu Senol A;Samarani M;Syan S;Guardia CM;Nonaka T;Liv N;Latour-Lambert P;Hasegawa M;Klumperman J;Bonifacino JS;Zurzolo C
α-突触核蛋白（α-syn）聚集体在特定脑区的积聚是包括帕金森病（PD）在内的突触核蛋白病的标志。α-Syn聚集体以“朊病毒样”方式繁殖，并且可以通过隧道纳米管（TNT）在溶酶体内转移到受体细胞。然而，溶酶体如何参与α-syn聚集体的扩散尚不清楚。在这里，通过使用超分辨率（SR）和电子显微镜（EM），我们发现α-syn纤维影响溶酶体的形态并损害其在神经元细胞中的功能。此外，我们证明α-syn纤维诱导溶酶体的外周再分布，可能由转录因子EB（TFEB）介导，增加α-syn纤维转移到邻近细胞的效率。我们还表明，溶酶体膜透化（LMP）允许可溶性α-syn接种在细胞中，已经采取了α-syn纤维从培养基中，更重要的是，在健康的细胞共培养后，溶酶体介导的转移纤维。此外，我们证明接种主要发生在供体和受体细胞的溶酶体中，分别在从培养基中摄取α-syn纤维后和转移后。最后，通过使用异型共培养系统，我们确定了细胞之间转移的溶酶体的来源和性质，我们表明携带α-syn纤维的供体细胞将受损的溶酶体转移到受体细胞，同时也从它们那里接收健康的溶酶体。因此，这些发现有助于阐明α-syn纤维通过TNT传播的机制，同时也揭示了溶酶体的关键作用，作为疾病病理学的播种和传播的特洛伊木马。这项研究表明，被α-突触核蛋白原纤维损伤的溶酶体成为播种新聚集体的枢纽，并发挥特洛伊木马的作用，通过隧道纳米管促进错误折叠的传播和聚集体在细胞之间的传播。
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. This study shows that lysosomes damaged by α-synuclein fibrils become a hub for seeding new aggregates and function as a Trojan horse, facilitating the propagation of misfolding and the dissemination of aggregates between cells through tunneling nanotubes.
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影响因子：
6.1
作者：
Chu, Yaping;Dodiya, Hemraj;Kordower, Jeffrey H.
通讯作者：
Kordower, Jeffrey H.
影响因子：
3.7
作者：
Angot E;Steiner JA;Lema Tomé CM;Ekström P;Mattsson B;Björklund A;Brundin P
通讯作者：
Brundin P
影响因子：
--
作者：
Abounit, Saida;Delage, Elise;Zurzolo, Chiara
通讯作者：
Zurzolo, Chiara
DOI：
10.1083/jcb.201408056
发表时间：
2015-02-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bentley M;Decker H;Luisi J;Banker G
通讯作者：
Banker G
影响因子：
16.6
作者：
Bae, Eun-Jin;Yang, Na-Young;Song, Miyoung;Lee, Cheol Soon;Lee, Jun Sung;Jung, Byung Chul;Lee, He-Jin;Kim, Seokjoong;Masliah, Eliezer;Sardi, Sergio Pablo;Lee, Seung-Jae
通讯作者：
Lee, Seung-Jae