Tau isoform expression and regulation in human cortical neurons
Tau isoform expression and regulation in human cortical neurons
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DOI：
10.1096/fj.07-096909
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发表时间：
2008-07-01
期刊：
影响因子：
4.8
通讯作者：
Busciglio, Jorge
中科院分区：
文献类型：
--
作者：
Deshpande, Atul;Win, Khin May;Busciglio, Jorge
tau 蛋白的差异表达、活性、磷酸化和寡聚化在神经元发育和许多与年龄相关的神经退行性疾病中发挥着关键作用。准确模拟 tau 蛋白病相关分子变化（特别是 tau 异构体活性变化）的实验系统需要在生理水平上表达成人大脑中存在的全部 tau 异构体。为此，我们分析了培养物中人类皮质神经元 (HCN) 的 tau 表达。在这里，我们发现 HCN 中 tau 的异构体特征与成人大脑中的相似，并且异构体的表达在神经元发育过程中受到细胞底物的调节。有趣的是，4R tau 表现出独特的表达模式和亚细胞定位，表明 tau 亚型在 HCN 中存在特定的功能作用。 tau 定向磷酸酶活性的药理学操作显着改变了 tau 磷酸化、微管结合和亚细胞定位，这也诱导了 tau 病动物模型中与记忆丧失相关的 tau 寡聚形式的出现。因此，实验诱导的 HCN 中 tau 活性和功能的变化概括了可能导致人脑神经元功能障碍和退化的 tau 病的关键特征。
Differential expression, activity, phosphorylation, and oligomerization of tau play a critical role during neuronal development and in a number of age-related neurodegenerative diseases. An experimental system that accurately models the molecular changes involved in tauopathies, particularly changes in tau isoform activity, requires the expression at physiological levels of the full complement of tau isoforms present in the adult human brain. To this end, we analyzed tau expression in human cortical neurons (HCNs) in culture. Here, we show that the isoform profile of tau in HCNs is similar to that in the adult human brain and that isoform expression is regulated during neuronal development and by cellular substrates. Interestingly, 4R tau exhibited a distinct pattern of expression and subcellular localization, suggesting the presence of specific functional roles for tau isoforms in HCNs. Tau phosphorylation, microtubule binding, and subcellular localization were markedly altered by pharmacological manipulation of tau-directed phosphatase activities, which also induced the appearance of tau oligomeric forms associated with memory loss in animal models of tauopathy. Thus, experimentally induced changes in tau activity and function in HCNs recapitulate critical features of tauopathies that may lead to neuronal dysfunction and degeneration in the human brain.