Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA.
Mol Neurodegener. 2009 May 2;4:18. doi: 10.1186/1750-1326-4-18.
Tau protein exists as six different isoforms that differ by the inclusion or exclusion of exons 2, 3 and 10. Exon 10 encodes a microtubule binding repeat, thereby resulting in three isoforms with three microtubule binding repeats (3R) and three isoforms that have four microtubule binding repeats (4R). In normal adult brain, the relative amounts of 3R tau and 4R tau are approximately equal. These relative protein levels are preserved in Alzheimer's disease, although in other neurodegenerative tauopathies such as progressive supranuclear palsy, corticobasal degeneration and Pick's disease, the ratio of 3R:4R is frequently altered. Because tau isoforms are not equally involved in these diseases, it is possible that they either have inherently unique characteristics owing to their primary structures or that post-translational modification, such as phosphorylation, differentially affects their properties.
We have determined the effects of phosphorylation by a kinase widely believed to be involved in neurodegenerative processes, glycogen synthase kinase-3beta (GSK-3beta), on the microtubule binding and inducer-initiated polymerization of these isoforms in vitro. We have found that each isoform has a unique microtubule binding and polymerization profile that is altered by GSK-3beta. GSK-3beta phosphorylation had differential effects on the isoforms although there were similarities between isoforms and the effects were generally mild.
These results indicate that tau phosphorylation by a single kinase can have isoform specific outcomes. The mild nature of these changes, however, makes it unlikely that differential effects of GSK-3beta phosphorylation on the isoforms are causative in neurodegenerative disease. Instead, the inherent differences in the isoform interactions themselves and local conditions in the diseased cells are likely the major determinant of isoform involvement in various neurodegenerative disorders.
Tau 蛋白有六种不同的异构体，它们通过包含或排除外显子 2、3 和 10 而有所不同。外显子 10 编码微管结合重复序列，从而导致具有三个微管结合重复序列 (3R) 的三种异构体和具有四个微管结合重复序列 (4R) 的三种异构体。在正常成年大脑中，3R tau 和 4R tau 的相对含量大致相等。这些相对蛋白质水平在阿尔茨海默病中得以保留，尽管在其他神经退行性 tau 病如进行性核上性麻痹、皮质基底节变性和匹克病中，3R:4R 的比值经常发生改变。由于 tau 异构体在这些疾病中并非同等参与，因此它们可能由于其一级结构而具有内在的独特特征，或者翻译后修饰，如磷酸化，对其性质产生不同的影响。
我们已经确定了一种广泛认为与神经退行性过程有关的激酶，糖原合酶激酶-3β（GSK-3β）对这些异构体在体外的微管结合和诱导剂引发聚合的磷酸化作用。我们发现，每种异构体都有独特的微管结合和聚合特性，这种特性会被 GSK-3β改变。GSK-3β磷酸化对异构体有不同的影响，尽管异构体之间存在相似之处，而且影响通常较为温和。
这些结果表明，单一激酶对 tau 的磷酸化可以产生异构体特异性的结果。然而，这些变化的温和性质使得 GSK-3β 磷酸化对异构体的差异影响在神经退行性疾病中不太可能是致病的。相反，异构体相互作用本身的固有差异以及患病细胞中的局部条件可能是决定异构体在各种神经退行性疾病中参与的主要因素。
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