Differential Effects of Tau on the Integrity and Function of Neurons Essential for Learning in Drosophila
Differential Effects of Tau on the Integrity and Function of Neurons Essential for Learning in Drosophila
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DOI：
10.1523/jneurosci.1490-09.2010
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发表时间：
2010-01-13
影响因子：
5.3
通讯作者：
Skoulakis, Efthimios M. C.
中科院分区：
文献类型：
--
作者：
Kosmidis, Stylianos;Grammenoudi, Sofia;Skoulakis, Efthimios M. C.
Tau病是一种异质性的神经退行性痴呆，涉及微管结合蛋白Tau的水平、磷酸化或突变的扰动。人类和模式生物的异质性病理学表明，神经元类型对野生型（WT）和突变型Tau的易感性存在差异。在果蝇中枢神经系统中全神经元表达的WT和突变型人类编码Tau的转基因在产生蘑菇体（MB）神经元的胚胎神经母细胞中产生特异性和差异性毒性，表明Tau在中枢神经系统中具有细胞类型特异性作用。额颞叶痴呆伴帕金森-17相关突变亚型在MB发展中的毒性显著降低。Tau过度磷酸化是这些MB畸变的必要条件，我们在WT hTau上发现了两个新的假定磷酸化位点，Ser（238）和Thr(245)，它们对MB完整性的毒性作用至关重要。值得注意的是，阻断假定的Ser（238）和Thr（245）磷酸化会产生表面上结构正常但功能严重失调的mb，因为积累这种突变蛋白的动物表现出强烈受损的联想学习。有趣的是，突变蛋白在通常与毒性和神经变性相关的表位上被过度磷酸化，如AT8、AT100和Par-1靶点Ser（262）和Ser(356)，这表明这些位点在成人完整mb的背景下介导功能障碍，这些位点的占领可能先于毒性相关的Ser（238）和Thr（245）磷酸化。这些数据支持这样一种观点，即特定位点的磷酸化而不是过度磷酸化本身以细胞类型特异性的方式介导毒性或功能障碍。
Tauopathies are a heterogeneous group of neurodegenerative dementias involving perturbations in the levels, phosphorylation, or mutations of the microtubule-binding protein Tau. The heterogeneous pathology in humans and model organisms suggests differential susceptibility of neuronal types to wild-type (WT) and mutant Tau. WT and mutant human Tau-encoding transgenes expressed panneuronally in the Drosophila CNS yielded specific and differential toxicity in the embryonic neuroblasts that generate the mushroom body (MB) neurons, suggesting cell type-specific effects of Tau in the CNS. Frontotemporal dementia with parkinsonism-17-linked mutant isoforms were significantly less toxic in MB development. Tau hyperphosphorylation was essential for these MB aberrations, and we identified two novel putative phosphorylation sites, Ser(238) and Thr(245), on WT hTau essential for its toxic effects on MB integrity. Significantly, blocking putative Ser(238) and Thr(245) phosphorylation yielded animals with apparently structurally normal but profoundly dysfunctional MBs, because animals accumulating this mutant protein exhibited strongly impaired associative learning.Interestingly, the mutant protein was hyperphosphorylated at epitopes typically associated with toxicity and neurodegeneration, such as AT8, AT100, and the Par-1 targets Ser(262) and Ser(356), suggesting that these sites in the context of adult intact MBs mediate dysfunction and occupation of these sites may precede the toxicity-associated Ser(238) and Thr(245) phosphorylation. The data support the notion that phosphorylation at particular sites rather than hyperphosphorylation per se mediates toxicity or dysfunction in a cell type-specific manner.