Galectin-8-mediated selective autophagy protects against seeded tau aggregation.
Galectin-8-mediated selective autophagy protects against seeded tau aggregation.
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DOI：
10.1074/jbc.m117.809293
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发表时间：
2018-02-16
期刊：
影响因子：
--
通讯作者：
Goedert M
中科院分区：
文献类型：
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作者：
Falcon B;Noad J;McMahon H;Randow F;Goedert M
组装的 tau 蛋白可以在细胞之间转移并引发可溶性 tau 蛋白的聚集。这一过程被认为是神经退行性疾病（包括阿尔茨海默病）中 tau 蛋白包涵体在整个大脑中扩增和传播的基础。了解所涉及的机制可能会提供限制组装 tau 传播的策略。在这里，我们试图确定组装的 tau 种子如何进入细胞质，以及这种进入是否会触发细胞防御。我们发现 tau 蛋白组装体通过网格蛋白独立的内吞作用进入细胞，并从受损的内膜逃逸到细胞质中，在那里它们播种可溶性 tau 蛋白的聚集。我们还发现危险受体半乳糖凝集素 8 可以检测受损的内膜，并通过招募货物受体核点蛋白 52 (NDP52) 来激活自噬。抑制半乳糖凝集素 8 和 NDP52 依赖性自噬会增加种子 tau 聚集，这表明在组装 tau 种子进入过程中，受损内膜触发的自噬可以防止 tau 聚集，其方式类似于细胞针对胞质溶胶中微生物的防御。第二个自噬货物受体 p62，然后靶向种子 tau 聚集体。我们的结果表明，通过监测内膜完整性，细胞可以减少 tau 种子进入细胞质，从而防止种子聚集。这里描述的机制可能有助于开发旨在抑制神经退行性疾病中蛋白质组装体传播的疗法。
Assembled tau can transfer between cells and seed the aggregation of soluble tau. This process is thought to underlie the amplification and propagation of tau inclusions throughout the brain in neurodegenerative diseases, including Alzheimer's disease. An understanding of the mechanisms involved may provide strategies for limiting assembled tau propagation. Here, we sought to determine how assembled tau seeds gain access to the cytosol and whether this access triggers cellular defenses. We show that tau assemblies enter cells through clathrin-independent endocytosis and escape from damaged endomembranes into the cytosol, where they seed the aggregation of soluble tau. We also found that the danger receptor galectin-8 detects damaged endomembranes and activates autophagy through recruitment of the cargo receptor nuclear dot protein 52 (NDP52). Inhibition of galectin-8– and NDP52-dependent autophagy increased seeded tau aggregation, indicating that autophagy triggered by damaged endomembranes during the entry of assembled tau seeds protects against tau aggregation, in a manner similar to cellular defenses against cytosol-dwelling microorganisms. A second autophagy cargo receptor, p62, then targeted seeded tau aggregates. Our results reveal that by monitoring endomembrane integrity, cells reduce entry of tau seeds into the cytosol and thereby prevent seeded aggregation. The mechanisms described here may help inform the development of therapies aimed at inhibiting the propagation of protein assemblies in neurodegenerative diseases.