Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose
Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose
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DOI：
10.1038/s41598-018-35811-8
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发表时间：
2019-01-24
影响因子：
4.6
通讯作者：
Xiang, Wei
中科院分区：
文献类型：
--
作者：
Hoffmann, Anna-Carin;Minakaki, Georgia;Xiang, Wei
聚集的 α 突触核蛋白 (aSyn) 的细胞间传播被认为在 α 突触核蛋白病的进展中发挥重要作用。繁殖过程的关键步骤是细胞外aSyn 在受体细胞内的积累。在这里，我们研究了不同外源 aSyn 形式的贩运，并探讨了影响其在受体细胞中积累的机制。聚集的 aSyn 种类（寡聚物和原纤维）在受体细胞内表现出比 aSyn 单体更明显的积累。特别是，以聚集形式内化的细胞外aSyn能够引发内源性aSyn的聚集。摄取后，沿着内体到溶酶体和自噬体到溶酶体的途径检测到 aSyn。有趣的是，聚集的 aSyn 导致溶酶体活性受损，并伴随着扩张的溶酶体的积累。此外，自噬相关蛋白标记物的分析表明自噬体清除率降低。相反，受体细胞中的内吞途径、蛋白酶体活性和线粒体稳态并未受到显着影响。我们的数据表明，细胞外添加聚集的 aSyn 主要损害溶酶体活性，从而导致受体细胞内 aSyn 积累。重要的是，自噬诱导剂海藻糖可防止溶酶体改变并减弱 aSyn 暴露细胞内的 aSyn 积累。我们的研究强调了溶酶体对于 aSyn 病理学传播的重要性，从而提出这些细胞器作为干预靶点。
Cell-to-cell propagation of aggregated alpha synuclein (aSyn) has been suggested to play an important role in the progression of alpha synucleinopathies. A critical step for the propagation process is the accumulation of extracellular aSyn within recipient cells. Here, we investigated the trafficking of distinct exogenous aSyn forms and addressed the mechanisms influencing their accumulation in recipient cells. The aggregated aSyn species (oligomers and fibrils) exhibited more pronounced accumulation within recipient cells than aSyn monomers. In particular, internalized extracellular aSyn in the aggregated forms was able to seed the aggregation of endogenous aSyn. Following uptake, aSyn was detected along endosome-to-lysosome and autophagosome-to-lysosome routes. Intriguingly, aggregated aSyn resulted in lysosomal activity impairment, accompanied by the accumulation of dilated lysosomes. Moreover, analysis of autophagy-related protein markers suggested decreased autophagosome clearance. In contrast, the endocytic pathway, proteasome activity, and mitochondrial homeostasis were not substantially affected in recipient cells. Our data suggests that extracellularly added aggregated aSyn primarily impairs lysosomal activity, consequently leading to aSyn accumulation within recipient cells. Importantly, the autophagy inducer trehalose prevented lysosomal alterations and attenuated aSyn accumulation within aSyn-exposed cells. Our study underscores the importance of lysosomes for the propagation of aSyn pathology, thereby proposing these organelles as interventional targets.