Tau fibrils induce nanoscale membrane damage and nucleate cytosolic tau at lysosomes.
Tau fibrils induce nanoscale membrane damage and nucleate cytosolic tau at lysosomes.
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Tau 原纤维诱导纳米级膜损伤并在溶酶体中使胞质 tau 成核。
DOI：
10.1101/2023.08.28.555157
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Hurley,JamesH
中科院分区：
文献类型：
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作者：
Rose,Kevin;Jepson,Tyler;Shukla,Sankalp;Maya-Romero,Alex;Kampmann,Martin;Xu,Ke;Hurley,JamesH
朊病毒样蛋白聚集物的扩散是大脑中神经原纤维病变传播的主要假设，包括与阿尔茨海默病相关的tau内含物的扩散。tau种子的细胞摄取和随后细胞质tau的成核聚合的机制是该领域的主要问题，并且进入和成核机制之间的耦合潜力很少被探索。我们发现，在初代星形细胞和神经元中，tau种子的内吞作用导致它们在溶酶体中积累。这反过来导致溶酶体肿胀，脱酸和ESCRT蛋白募集，但不是半乳糖凝集素-3，溶酶体膜。这些观察结果与溶酶体膜的纳米级损伤一致。活细胞成像和STORM超分辨率显微镜进一步显示，在这些条件下，细胞质tau的成核主要发生在溶酶体膜上。这些数据表明，tau种子通过纳米级损伤而不是大规模破裂从溶酶体中逃逸，并且一旦tau纤维末端从溶酶体膜中出现，细胞质tau就开始成核。
The prion-like spread of protein aggregates is a leading hypothesis for the propagation of neurofibrillary lesions in the brain, including the spread of tau inclusions associated with Alzheimer’s disease. The mechanisms of cellular uptake of tau seeds and subsequent nucleated polymerization of cytosolic tau are major questions in the field, and the potential for coupling between the entry and nucleation mechanisms has been little explored. We found that in primary astrocytes and neurons, endocytosis of tau seeds leads to their accumulation in lysosomes. This in turn leads to lysosomal swelling, deacidification, and recruitment of ESCRT proteins, but not Galectin-3, to the lysosomal membrane. These observations are consistent with nanoscale damage of the lysosomal membrane. Live cell imaging and STORM superresolution microscopy further show that the nucleation of cytosolic tau occurs primarily at the lysosome membrane under these conditions. These data suggest that tau seeds escape from lysosomes via nanoscale damage rather than wholesale rupture and that nucleation of cytosolic tau commences as soon as tau fibril ends emerge from the lysosomal membrane.