Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs).
Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs).
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DOI：
10.1038/s41598-018-24904-z
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发表时间：
2018-04-23
影响因子：
4.6
通讯作者：
Kosik KS
中科院分区：
文献类型：
--
作者：
Rauch JN;Chen JJ;Sorum AW;Miller GM;Sharf T;See SK;Hsieh-Wilson LC;Kampmann M;Kosik KS
tau 蛋白错误折叠并积累成细胞内聚集体（称为神经原纤维缠结），是阿尔茨海默病等神经退行性疾病的病理标志。然而，虽然 tau 蛋白传播是疾病进展的已知标志物，但 tau 蛋白到底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 tau 的细胞内化受到四级结构的调节，并开发了一种细胞测定法来筛选 tau 摄取的遗传调节剂。利用 CRISPRi 技术，我们测试了 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作为关键调节因子。我们发现 6-O-硫酸化对于 tau-硫酸乙酰肝素相互作用至关重要，并且这种修饰调节人类中枢神经系统细胞系、iPS 衍生神经元和小鼠脑切片培养物的摄取。总之，这些结果提出了阻止 tau 传输的新策略。
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.
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影响因子：
15.1
作者：
Lasagna-Reeves CA;Castillo-Carranza DL;Sengupta U;Clos AL;Jackson GR;Kayed R
通讯作者：
Kayed R
影响因子：
14.8
作者：
通讯作者：
--
DOI：
10.1126/science.aah3374
发表时间：
2016-09-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Mao X;Ou MT;Karuppagounder SS;Kam TI;Yin X;Xiong Y;Ge P;Umanah GE;Brahmachari S;Shin JH;Kang HC;Zhang J;Xu J;Chen R;Park H;Andrabi SA;Kang SU;Gonçalves RA;Liang Y;Zhang S;Qi C;Lam S;Keiler JA;Tyson J;Kim D;Panicker N;Yun SP;Workman CJ;Vignali DA;Dawson VL;Ko HS;Dawson TM
通讯作者：
Dawson TM
影响因子：
2.9
作者：
Jeganathan, Sadasivam;von Bergen, Martin;Mandelkow, Eckhard
通讯作者：
Mandelkow, Eckhard
影响因子：
4.8
作者：
Mirbaha, Hilda;Holmes, Brandon B.;Diamond, Marc I.
通讯作者：
Diamond, Marc I.