MSUT2 modulates pathological tau in AD and model organisms

摘要： 含有异常聚集的tau蛋白的神经元病变构成了诊断性疾病之一。 阿尔茨海默病的标志、相关的tau蛋白病病症和大脑的晚期老化。在 阿尔茨海默病，tau神经病理学与痴呆的严重程度相关。然而 聚集的tau蛋白导致阿尔茨海默病神经元功能障碍和丧失的机制 疾病患者仍然是个谜。我们以前证明了一个保守的基因，称为sut- 2/MSUT 2控制C.线虫和人类细胞。初步研究 已经证明MSUT 2控制哺乳动物脑中神经元对tau毒性的易感性。 拟议的工作将验证这些发现，并探索MSUT 2 作用于调节tau蛋白病疾病机制。尽管MSUT 2似乎与RNA结合， MSUT 2调节tau蛋白病的分子机制仍不清楚。具体目标是 项目是：1）表征tau蛋白病小鼠模型中MSUT 2敲除的后果。 2)确定增加的MSUT 2活性对tau神经病理学和行为表型的影响 对小鼠3)剖析MSUT 2调节tau蛋白病的分子机制。完成 所提出的项目将证明MSUT 2在tau蛋白病中的重要性。我们也将获得 对涉及tau病理学的MSUT 2调节的分子机制的重要理解 在不同的生物体中，从C. elegans to humans人类.这些知识将为未来奠定基础 通过提供用于药理学干预的新的候选治疗靶点进行翻译研究。

Abstract: Neuronal lesions containing abnormal aggregated tau protein constitute one of the diagnostic hallmarks of Alzheimer's disease, related tauopathy disorders, and advanced aging of the brain. In Alzheimer's disease, tau neuropathology correlates with severity of dementia. However the mechanisms by which aggregated tau leads to the dysfunction and loss of neurons in Alzheimer's disease patients remain enigmatic. We previously demonstrated that a conserved gene called sut- 2/MSUT2 controls tau aggregation and toxicity in C. elegans and human cells. Preliminary studies have demonstrated that MSUT2 controls neuronal susceptibility to tau toxicity in the mammalian brain. The proposed work will verify these findings and explore the molecular underpinnings by which MSUT2 acts to modulate tauopathy disease mechanisms. Although MSUT2 appears to bind RNA, the molecular mechanisms of MSUT2 modulation of tauopathy remains unclear. The Specific Aims of this project are to: 1) Characterize the consequences of MSUT2 knockout in mouse models of tauopathy. 2) Determine the effect of increased MSUT2 activity on tau neuropathology and behavioral phenotypes in mice. 3) Dissect the molecular mechanisms of MSUT2 modulation of tauopathy. Completion of the project as proposed will demonstrate the importance of MSUT2 in tauopathy. We will also gain significant understanding of the molecular mechanisms involved in MSUT2 modulation of tau pathology in diverse organisms ranging from C. elegans to humans. This knowledge will set the stage for future translational studies by providing novel candidate therapeutic targets for pharmacological intervention.