tau 内吞作用受硫酸乙酰肝素蛋白聚糖 (HSPGs) 6-O 位磺酸化调控。
Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs).
机构信息
Neuroscience Research Institute, Department of Molecular Cellular Developmental Biology, University of California, Santa Barbara, CA, 93106, USA.
Institute for Neurodegenerative Diseases, Department of Biochemistry & Biophysics, The California Institute for Quantitative Biomedical Research, Quantitative Biosciences Institute, University of California, San Francisco, and Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA.
出版信息
Sci Rep. 2018 Apr 23;8(1):6382. doi: 10.1038/s41598-018-24904-z.
The misfolding and accumulation of tau protein into intracellular aggregates known as neurofibrillary tangles is a pathological hallmark of neurodegenerative diseases such as Alzheimer's disease. However, while tau propagation is a known marker for disease progression, exactly how tau propagates from one cell to another and what mechanisms govern this spread are still unclear. Here, we report that cellular internalization of tau is regulated by quaternary structure and have developed a cellular assay to screen for genetic modulators of tau uptake. Using CRISPRi technology we have tested 3200 genes for their ability to regulate tau entry and identified enzymes in the heparan sulfate proteoglycan biosynthetic pathway as key regulators. We show that 6-O-sulfation is critical for tau-heparan sulfate interactions and that this modification regulates uptake in human central nervous system cell lines, iPS-derived neurons, and mouse brain slice culture. Together, these results suggest novel strategies to halt tau transmission.
tau 蛋白错误折叠并积累成细胞内聚集体，即神经原纤维缠结，这是阿尔茨海默病等神经退行性疾病的病理学标志。然而，虽然 tau 传播是疾病进展的已知标志物，但 tau 如何从一个细胞传播到另一个细胞，以及控制这种传播的机制仍不清楚。在这里，我们报告说 tau 的细胞内摄取受四级结构调节，并开发了一种细胞测定法来筛选 tau 摄取的遗传调节剂。我们使用 CRISPRi 技术测试了 3200 个基因调节 tau 进入的能力，并确定了硫酸乙酰肝素蛋白聚糖生物合成途径中的酶是关键调节因子。我们表明 6-O-硫酸化对于 tau-硫酸乙酰肝素相互作用至关重要，并且这种修饰调节了人中枢神经系统细胞系、iPS 衍生神经元和小鼠脑片培养物中的摄取。总之，这些结果表明了阻止 tau 传播的新策略。
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