Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis.
Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis.
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DOI：
10.1371/journal.pone.0062143
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Campbell EM
中科院分区：
文献类型：
--
作者：
Freeman D;Cedillos R;Choyke S;Lukic Z;McGuire K;Marvin S;Burrage AM;Sudholt S;Rana A;O'Connor C;Wiethoff CM;Campbell EM
α-突触核蛋白失调是帕金森病病理学的一个重要方面。最近的研究已经观察到α-突触核蛋白聚集体对培养物中的细胞具有细胞毒性，并且这种毒性可以在细胞之间传播。然而，这种细胞毒性和扩散的分子机制的特点很差。最近的研究病毒和细菌，实现其细胞质的进入，通过破裂细胞内囊泡，利用半乳糖凝集素蛋白的再分布作为一种工具来衡量这些生物体囊泡破裂。使用这种方法，我们证明了α-突触核蛋白聚集体可以诱导神经元细胞系中溶酶体内吞后破裂。这种断裂可以通过将α-突触核蛋白聚集体直接加入细胞以及通过α-突触核蛋白的细胞间转移来诱导。我们还观察到α-突触核蛋白引起的溶酶体破裂诱导靶细胞中活性氧（ROS）的组织蛋白酶B依赖性增加。最后，我们观察到α-突触核蛋白聚集体可以诱导THP-1细胞中的炎性小体活化。已知溶酶体破裂会诱导线粒体功能障碍和炎症，这两者都是帕金森病的公认方面，因此将帕金森病的这些方面与细胞中α-突触核蛋白病理学的传播联系起来。
α-synuclein dysregulation is a critical aspect of Parkinson's disease pathology. Recent studies have observed that α-synuclein aggregates are cytotoxic to cells in culture and that this toxicity can be spread between cells. However, the molecular mechanisms governing this cytotoxicity and spread are poorly characterized. Recent studies of viruses and bacteria, which achieve their cytoplasmic entry by rupturing intracellular vesicles, have utilized the redistribution of galectin proteins as a tool to measure vesicle rupture by these organisms. Using this approach, we demonstrate that α-synuclein aggregates can induce the rupture of lysosomes following their endocytosis in neuronal cell lines. This rupture can be induced by the addition of α-synuclein aggregates directly into cells as well as by cell-to-cell transfer of α-synuclein. We also observe that lysosomal rupture by α-synuclein induces a cathepsin B dependent increase in reactive oxygen species (ROS) in target cells. Finally, we observe that α-synuclein aggregates can induce inflammasome activation in THP-1 cells. Lysosomal rupture is known to induce mitochondrial dysfunction and inflammation, both of which are well established aspects of Parkinson's disease, thus connecting these aspects of Parkinson's disease to the propagation of α-synuclein pathology in cells.
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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：
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30.5
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影响因子：
2.9
作者：
Di Lella, Santiago;Sundblad, Victoria;Cerliani, Juan P.;Guardia, Carlos M.;Estrin, Dario A.;Vasta, Gerardo R.;Rabinovich, Gabriel A.
通讯作者：
Rabinovich, Gabriel A.