MSUT2 is a determinant of susceptibility to tau neurotoxicity
MSUT2 is a determinant of susceptibility to tau neurotoxicity
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DOI：
10.1093/hmg/ddr079
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发表时间：
2011-05-15
影响因子：
3.5
通讯作者：
Kraemer, Brian C.
中科院分区：
文献类型：
--
作者：
Guthrie, Chris R.;Greenup, Lynne;Kraemer, Brian C.
含有异常聚集的tau蛋白的病变是阿尔茨海默病（AD）和相关tau蛋白病病症的诊断标志之一。聚集的tau蛋白如何导致痴呆仍然是个谜，尽管神经元功能障碍和损失显然是原因之一。我们以前确定sut-2作为tau蛋白病的转基因秀丽隐杆线虫模型中tau蛋白神经毒性所需的基因。在这里，我们进一步探讨了SUT-2的作用，并表明SUT-2蛋白的过表达增强了tau蛋白诱导的神经元功能障碍、神经毒性和不溶性tau蛋白的积累。我们还探讨了SUT-2和它的人类同源物，哺乳动物SUT-2（MSUT 2）之间的关系，并发现这两种蛋白质主要是核和本地化的SC 35阳性核斑点。使用病理性tau积累的细胞培养模型，我们发现高tau水平导致MSUT 2蛋白表达增加。我们分析了来自AD患者的年龄匹配的死后脑样本中的MSUT 2蛋白，并观察到AD患者颞叶中的总体MSUT 2水平显著降低。对AD病例的尸检组织的分析显示，在受tau病理影响的脑区域中神经元MSUT 2水平明显降低，但在缺乏tau病理的区域中几乎没有变化。在培养的过表达tau的人细胞中MSUT 2的RNAi敲低导致tau聚集的显著减少。细胞培养和死后组织研究都表明，MSUT 2水平可能影响神经元对tau毒性和聚集的脆弱性。因此，靶向MSUT 2的神经保护策略可能对tau蛋白病病症具有治疗意义。
Lesions containing abnormal aggregated tau protein are one of the diagnostic hallmarks of Alzheimer's disease (AD) and related tauopathy disorders. How aggregated tau leads to dementia remains enigmatic, although neuronal dysfunction and loss clearly contribute. We previously identified sut-2 as a gene required for tau neurotoxicity in a transgenic Caenorhabditis elegans model of tauopathy. Here, we further explore the role of sut-2 and show that overexpression of SUT-2 protein enhances tau-induced neuronal dysfunction, neurotoxicity and accumulation of insoluble tau. We also explore the relationship between sut-2 and its human homolog, mammalian SUT-2 (MSUT2) and find both proteins to be predominantly nuclear and localized to SC35-positive nuclear speckles. Using a cell culture model for the accumulation of pathological tau, we find that high tau levels lead to increased expression of MSUT2 protein. We analyzed MSUT2 protein in age-matched post-mortem brain samples from AD patients and observe a marked decrease in overall MSUT2 levels in the temporal lobe of AD patients. Analysis of post-mortem tissue from AD cases shows a clear reduction in neuronal MSUT2 levels in brain regions affected by tau pathology, but little change in regions lacking tau pathology. RNAi knockdown of MSUT2 in cultured human cells overexpressing tau causes a marked decrease in tau aggregation. Both cell culture and post-mortem tissue studies suggest that MSUT2 levels may influence neuronal vulnerability to tau toxicity and aggregation. Thus, neuroprotective strategies targeting MSUT2 may be of therapeutic interest for tauopathy disorders.