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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity
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Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity

机译：高磷酸化的tau聚合成细丝消除了其抑制活性

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Accumulation of abnormally hyperphosphorylated tau (P-tau) in the form of tangles of paired helical filaments and/or straight filaments is one of the hallmarks of Alzheimer's disease (AD) and other tauopathies. P-tau is also found unpolymerized in AD. Although the cognitive decline is known to correlate with the degree of neurofibrillary pathology, whether the formation of filaments or the preceding abnormal hyperphosphorylation of tau is the inhibitory entity that leads to neurodegeneration has been elusive. We have previously shown that cytosolic abnormaly hyperphosphorylated tau in AD brain (AD P-tau) sequesters normal tau (N-tau), microtubule-associated protein (MAP) 1, and MAP2, which results in the inhibition of microtubule assembly and disruption of microtubules. Here, we show that polymerization of AD P-tau into filaments inhibits its ability to bind N-tau and as well as the ability to inhibit the assembly of tubulin into microtubules in vitro and in the regenerating microtubule system from cultured cells. Like AD P-tau, the in vitro abnormally hyperphosphorylated recombinant brain N-tau binds N-tau and loses this binding activity on polymerization into filaments. Dissociation of the hyperphosphorylated N-tau filaments by ultrasonication restores its ability to bind N-tau. These findings suggest that the nonfibrillized P-tau is most likely the responsible entity for the disruption of microtubules in neurons in AD. The efforts in finding a therapeutic intervention for tau-induced neurodegeneration need to be directed either to prevent the abnormal hyperphosphorylation of this protein or to neutralize its binding to normal MAPs, rather than to prevent its aggregation into filaments.
机译：成对的螺旋丝和/或直丝缠结形式的异常高磷酸化tau（P-tau）积累是阿尔茨海默氏病（AD）和其他tauopathies的标志之一。在AD中也发现P-tau未聚合。尽管已知认知功能下降与神经原纤维病理学程度有关，但是否形成细丝或先前异常的tau过度磷酸化是导致神经退行性变的抑制实体，这一点尚不清楚。先前我们已经证明，AD脑中的胞浆异常高磷酸化tau（AD P-tau）隔离正常tau（N-tau），微管相关蛋白（MAP）1和MAP2，从而抑制了微管组装并破坏了Tau。微管。在这里，我们表明，AD P-tau聚合成细丝会抑制其结合N-tau的能力，以及抑制微管蛋白在体外和从培养细胞再生的微管系统中组装成微管的能力。像AD P-tau一样，体外异常磷酸化异常的重组脑N-tau会结合N-tau并在聚合成细丝时失去这种结合活性。通过超声使高磷酸化的N-tau细丝解离，恢复了其结合N-tau的能力。这些发现表明，未纤维化的P-tau最有可能是AD神经元微管破坏的原因。寻找针对tau诱导的神经变性的治疗性干预措施的努力既要防止该蛋白异常过度磷酸化，也要中和其与正常MAP的结合，而不是防止其聚集成细丝。

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