Tau was originally identified as a microtubule associated protein, and subsequently recognized to constitute the fibrillar assemblies found in Alzheimer disease and related neurodegenerative tauopathies. Point mutations in the microtubule associated protein tau (MAPT) gene cause dominantly inherited tauopathies, and most predispose it to aggregate. This indicates tau aggregation underlies pathogenesis of tauopathies. Our work has suggested that tau functions as a prion, forming unique intracellular pathological assemblies that subsequently move to other cells, inducing further aggregation that underlies disease progression. Remarkably, in simple cells tau forms stably propagating aggregates of distinct conformation, termed strains. Each strain induces a unique and, in some cases, transmissible, neuropathological phenotype upon inoculation into a mouse model. After binding heparan sulfate proteoglycans on the plasma membrane, tau assemblies enter cells via macropinocytosis. From within a vesicle, if not trafficked to the endolysosomal system, tau subsequently enters the cytoplasm, where it becomes a template for its own replication, apparently after processing by valosin containing protein. The smallest seed unit is a stable monomer, which suggests that initial folding events in tau presage subsequent pathological aggregation. The study of tau prions has raised important questions about basic cell biological processes that underlie their replication and propagation, with implications for therapy of tauopathies.

中文翻译：

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与 tau 朊病毒一起旅行

Tau 最初被鉴定为微管相关蛋白，随后被认为构成阿尔茨海默病和相关神经退行性 tau 病中发现的纤维组件。微管相关蛋白 tau (MAPT) 基因的点突变会导致显性遗传性 tau 蛋白病，并且大多数会导致其聚集。这表明 tau 蛋白聚集是 tau 蛋白病发病机制的基础。我们的工作表明，tau 蛋白具有朊病毒的功能，形成独特的细胞内病理组装体，随后转移到其他细胞，诱导进一步聚集，从而导致疾病进展。值得注意的是，在简单细胞中，tau 蛋白形成稳定繁殖的不同构象的聚集体，称为菌株。每种菌株在接种到小鼠模型中后都会诱导出独特的、在某些情况下可传播的神经病理学表型。在质膜上结合硫酸乙酰肝素蛋白聚糖后，tau 蛋白组装体通过巨胞饮作用进入细胞。从囊泡内，如果不被运输到内溶酶体系统，tau蛋白随后进入细胞质，在那里它成为其自身复制的模板，显然是在经过含有缬洛新蛋白的处理之后。最小的种子单元是稳定的单体，这表明 tau 蛋白的初始折叠事件预示着随后的病理性聚集。tau 朊病毒的研究提出了有关其复制和传播的基本细胞生物学过程的重要问题，这对 tau 蛋白病的治疗具有重要意义。