Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila
Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila
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DOI：
10.1093/hmg/ddm011
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发表时间：
2007-03-01
影响因子：
3.5
通讯作者：
Lecourtois, Magalie
中科院分区：
文献类型：
--
作者：
Blard, Olivier;Feuillette, Sebastien;Lecourtois, Magalie
tau蛋白病，包括阿尔茨海默病和与17号染色体（FTDP-17）相关的额颞叶痴呆和帕金森综合征，是一组以异常磷酸化tau蛋白的神经元内丝状包涵体的存在为特征的神经退行性疾病。Tau是一种神经元微管相关蛋白，参与微管组装和稳定。目前，tau蛋白介导的细胞毒性的分子机制仍然难以捉摸。为了解决tau神经毒性的决定因素，我们首先表征了果蝇中与FTDP-17相关的人tau突变形式（tau V337 M）的过度表达所导致的细胞改变。我们发现，过度表达的tau蛋白V337 M，在果蝇幼虫运动神经元，诱导破坏的微管网络突触前神经末梢和神经肌肉接头形态特征的变化。其次，我们进行了错误表达筛选，以确定tau V337 M介导的粗糙眼表型的遗传修饰剂。1250突变果蝇线的筛选，使我们能够确定几个组件的细胞骨架，特别是从肌动蛋白网络，作为特定的修饰剂的tau V337 M诱导的神经变性。此外，我们发现在我们的筛选中鉴定的许多tau调节剂参与突触功能的维持。总之，这些发现表明，突触前神经末梢中微管网络的破坏可能构成导致tau V337 M病理学中突触功能障碍的病理过程中的早期事件。
Tauopathies, including Alzheimer's disease and fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), are a group of neurodegenerative disorders characterized by the presence of intraneuronal filamentous inclusions of aberrantly phosphorylated-tau. Tau is a neuronal microtubule-associated protein involved in microtubule assembly and stabilization. Currently, the molecular mechanisms underlying tau-mediated cellular toxicity remain elusive. To address the determinants of tau neurotoxicity, we first characterized the cellular alterations resulting from the over-expression of a mutant form of human tau associated with FTDP-17 (tau V337M) in Drosophila. We found that the over-expression of tau V337M, in Drosophila larval motor neurons, induced disruption of the microtubular network at presynaptic nerve terminals and changes in neuromuscular junctions morphological features. Secondly, we performed a misexpression screen to identify genetic modifiers of the tau V337M-mediated rough eye phenotype. The screening of 1250 mutant Drosophila lines allowed us to identify several components of the cytoskeleton, and particularly from the actin network, as specific modifiers of tau V337M-induced neurodegeneration. Furthermore, we found that numerous tau modulators identified in our screen were involved in the maintenance of synaptic function. Taken together, these findings suggest that disruption of the microtubule network in presynaptic nerve terminals could constitute early events in the pathological process leading to synaptic dysfunction in tau V337M pathology.