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首页> 美国卫生研究院文献>PLoS Genetics >Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity
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Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity

机译：通过Par-1 / MARK在Ser262 / 356处通过Tau磷酸化使微管未结合的Tau稳定有助于增强AD相关磷酸化和Aβ42诱导的Tau毒性。

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Abnormal accumulation of the microtubule-interacting protein tau is associated with neurodegenerative diseases including Alzheimer’s disease (AD). β-amyloid (Aβ) lies upstream of abnormal tau behavior, including detachment from microtubules, phosphorylation at several disease-specific sites, and self-aggregation into toxic tau species in AD brains. To prevent the cascade of events leading to neurodegeneration in AD, it is essential to elucidate the mechanisms underlying the initial events of tau mismetabolism. Currently, however, these mechanisms remain unclear. In this study, using transgenic Drosophila co-expressing human tau and Aβ, we found that tau phosphorylation at AD-related Ser262/356 stabilized microtubule-unbound tau in the early phase of tau mismetabolism, leading to neurodegeneration. Aβ increased the level of tau detached from microtubules, independent of the phosphorylation status at GSK3-targeted SP/TP sites. Such mislocalized tau proteins, especially the less phosphorylated species, were stabilized by phosphorylation at Ser262/356 via PAR-1/MARK. Levels of Ser262 phosphorylation were increased by Aβ42, and blocking this stabilization of tau suppressed Aβ42-mediated augmentation of tau toxicity and an increase in the levels of tau phosphorylation at the SP/TP site Thr231, suggesting that this process may be involved in AD pathogenesis. In contrast to PAR-1/MARK, blocking tau phosphorylation at SP/TP sites by knockdown of Sgg/GSK3 did not reduce tau levels, suppress tau mislocalization to the cytosol, or diminish Aβ-mediated augmentation of tau toxicity. These results suggest that stabilization of microtubule-unbound tau by phosphorylation at Ser262/356 via the PAR-1/MARK may act in the initial steps of tau mismetabolism in AD pathogenesis, and that such tau species may represent a potential therapeutic target for AD.
机译：微管相互作用蛋白tau的异常积累与包括阿兹海默氏病（AD）在内的神经退行性疾病有关。 β-淀粉样蛋白（Aβ）位于tau异常行为的上游，包括从微管脱落，在几个疾病特异性部位的磷酸化以及在AD脑中自我聚集成有毒的tau物种。为了防止导致AD发生神经退行性变的事件级联，必须阐明tau代谢代谢初期事件的潜在机制。但是，目前，这些机制仍不清楚。在这项研究中，使用共表达人类tau和Aβ的转基因果蝇，我们发现在AD相关的Ser262 / 356上，tau磷酸化在tau代谢不良的早期稳定了微管未结合的tau，导致神经变性。 Aβ增加了与微管分离的tau的水平，与GSK3靶向的SP / TP位点的磷酸化状态无关。这样的错位tau蛋白，尤其是磷酸化程度较低的蛋白，通过PAR-1 / MARK在Ser262 / 356处的磷酸化作用得以稳定。 Aβ42增加了Ser262磷酸化的水平，并阻断了tau的这种稳定作用，抑制了Aβ42介导的tau毒性增强和SP / TP位点Thr231上tau磷酸化水平的增加，表明该过程可能与AD发病有关。与PAR-1 / MARK相比，通过敲低Sgg / GSK3阻止SP / TP位点的tau磷酸化不会降低tau的水平，不会抑制tau在细胞质中的定位错误，或减少Aβ介导的tau毒性增强。这些结果表明，通过PAR-1 / MARK在Ser262 / 356处的磷酸化作用使微管未结合的tau稳定化，可能在tau代谢不良的AD发病机理的初始步骤中起作用，并且这种tau物种可能代表了AD的潜在治疗靶点。

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