Chin J Y, Knowles R B, Schneider A, Drewes G, Mandelkow E M, Hyman B T
Alzheimer's Disease Research Unit, Massachusetts General Hospital East, Charlestown 02129, USA.
J Neuropathol Exp Neurol. 2000 Nov;59(11):966-71. doi: 10.1093/jnen/59.11.966.
Paired helical filaments, the main structural components of the neurofibrillary tangles in Alzheimer disease, consist of phosphorylated tau protein. Because the levels and degree of phosphorylation are significantly higher in paired helical filament (PHF)-derived tau than in normal adult tau, and because phosphorylation of tau severely disrupts microtubule stability, it is postulated that tau phosphorylation is an important step in PHF formation. The kinases and/or phosphatases that act in vivo to help induce such a pathological state of tau, however, are not yet known. In this study we implicate the non-proline directed kinase MARK in PHF-tau phosphorylation, by virtue of its close intermolecular association with the phosphorylated Ser262 epitope on PHF-tau as assessed by fluorescence resonance energy transfer. Moreover, because this tight enzyme-substrate association is observed in neurofibrillary tangles in Alzheimer tissue, we suggest that PHF-tau phosphorylation may occur to some extent on assembled PHF filaments.
成对螺旋丝是阿尔茨海默病神经原纤维缠结的主要结构成分，由磷酸化的tau蛋白组成。由于成对螺旋丝（PHF）衍生的tau蛋白中磷酸化的水平和程度显著高于正常成年tau蛋白，并且由于tau蛋白的磷酸化严重破坏微管稳定性，因此推测tau蛋白磷酸化是PHF形成的重要步骤。然而，在体内作用以帮助诱导tau蛋白这种病理状态的激酶和/或磷酸酶尚不清楚。在本研究中，我们通过荧光共振能量转移评估发现，非脯氨酸定向激酶MARK与PHF-tau上磷酸化的Ser262表位紧密分子间结合，从而表明MARK参与PHF-tau的磷酸化。此外，由于在阿尔茨海默病组织的神经原纤维缠结中观察到这种紧密的酶-底物结合，我们认为PHF-tau磷酸化可能在一定程度上发生在组装好的PHF细丝上。
