Novel model of secreted human tau protein reveals the impact of the abnormal N-glycosylation of tau on its aggregation propensity
Novel model of secreted human tau protein reveals the impact of the abnormal N-glycosylation of tau on its aggregation propensity
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DOI：
10.1038/s41598-019-39218-x
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发表时间：
2019-02-19
影响因子：
4.6
通讯作者：
Segal, Daniel
中科院分区：
文献类型：
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作者：
Losev, Yelena;Paul, Ashim;Segal, Daniel
阿尔茨海默病（AD）是最常见的神经退行性疾病，目前尚无改善疾病的治疗方法。AD的标志是两种淀粉样蛋白：tau和淀粉样蛋白。Tau经历几种翻译后修饰，包括N-糖基化。据报道，Tau在AD脑中是N-糖基化的，但在健康对应物中不是，这可能影响AD病因。在这里，我们的目的是检查N-糖基化对tau聚集倾向的影响。为此，产生了一种新的基于SH-SY 5 Y细胞的模型，其中重组人tau（htau）被迫从细胞中分泌。发现分泌的htau定位于分泌途径隔室中并进行N-糖基化。在分泌的htau的N-聚糖裂解后，各种生物物理结果共同表明，与经处理的去糖基化分泌的htau相比，未经处理的N-糖基化分泌的htau的聚集性显著降低，含有更细和更短的原纤维。这一发现表明，与htau连接的N-聚糖可能影响其聚集。这可能有助于更好地理解N-糖基化htau对AD进展的影响。
Alzheimer's disease (AD) is the most common neurodegenerative disorder and has no disease-modifying treatment yet. The hallmarks of AD are two amyloidogenic proteins: tau and amyloid. Tau undergoes several posttranslational modifications, including N-glycosylation. Tau was reported to be N-glycosylated in AD brains, but not in healthy counterparts, which may affect AD etiology. Here, we aimed to examine the effect of N-glycosylation on aggregation propensity of tau. To that end, a novel SH-SY5Y cell-based model was generated in which recombinant human tau (htau) is forced to be secreted from the cells. Secreted htau was found to localize in the secretory pathway compartments and to undergo N-glycosylation. Following N-glycan cleavage of the secreted htau, various biophysical results collectively indicated that the untreated N-glycosylated secreted htau is markedly less aggregative, contains thinner and shorter fibrils, as compared to treated de-glycosylated secreted htau. This finding shows that N-glycans attached to htau may affect its aggregation. This could help to better understand the effect of N-glycosylated htau on AD progression.