SPOP drives neurodegenerative tauopathy

摘要： 聚集的病理性tau蛋白构成阿尔茨海默病（AD）的诊断标志之一， 相关疾病（ADRD）。病理性tau蛋白引起功能障碍的分子机制， 神经元的变性仍然不完全清楚。然而，病理性tau蛋白驱动的神经元 功能障碍和神经变性明显地导致痴呆。为了研究病理性tau蛋白如何导致 在AD和ADRD的神经退行性变中，我们建立了C.神经退行性变的秀丽线虫 由人类tau蛋白聚集驱动。在我们以前的工作中，我们鉴定了几个控制tau毒性的基因， C.包括sut-1、sut-2、parn-2、sut-6、aly-1、aly-2和aly-3;所有这些基因都具有共同的 编码蛋白质存在于核斑点内的特性。核斑点是无膜细胞器 在细胞核内作为RNA加工的枢纽。我们以前的翻译工作 实验室和其他人已经表明AD/ADRD表现出RNA加工缺陷和 几种核斑点蛋白，包括MSUT 2、PABPN 1和SRRM 2。我们利用了我们的C。elegans tau蛋白病模型，开始剖析核斑点在tau蛋白病中的功能作用。我们找到了tau 介导的神经元功能障碍和神经退行性变可以通过核斑点驻留E3的丢失来挽救 泛蛋白连接酶衔接蛋白，称为SPOP。我们假设SPOP介导的底物降解 蛋白质影响核斑点的动力学和液-液相分离，以调节 病理性tau蛋白鉴于核斑点蛋白和RNA加工的高度保守性， 哺乳动物与C. elegans，我们建议利用C.线虫和转基因小鼠 tau蛋白病模型，以剖析SPOP功能丧失对tau蛋白的保护作用的分子机制 神经毒性本课题的具体目的是：1）明确SPOP对神经元核内信号传导的影响 Tau病变中斑点组成和动力学。2)鉴别关键非降解性CUL 3SPOP E3连接酶 参与tau蛋白病的泛素化底物。3)探索关键CUL 3SPOP底物的作用 在人类疾病和tau蛋白病的小鼠模型中的蛋白质。通过完成拟议的工作，我们 将发展新的疾病机制的分子理解，核斑点和SPOP 蛋白质参与tau蛋白病。这项工作也将提供第一个翻译的努力，了解是否 核斑点的靶向变化可以保护神经元免受哺乳动物脑中病理性tau的影响。

Abstract: Aggregated pathological tau protein constitutes one of the diagnostic hallmarks of Alzheimer’s disease (AD) and related disorders (ADRD). The molecular mechanisms by which pathological tau causes dysfunction and degeneration of neurons remains incompletely understood. However, pathological tau driven neuronal dysfunction and neurodegeneration clearly cause dementia. To investigate how pathological tau contributes to neurodegeneration in AD and ADRD, we established a transgenic model in C. elegans for neurodegeneration driven by human tau aggregation. In our previous work, we identified several genes that control tau toxicity in C. elegans including sut-1, sut-2, parn-2, sut-6, aly-1, aly-2, and aly-3; all of these genes share the common property of encoding proteins residing within nuclear speckles. Nuclear speckles are membraneless organelles within the cell’s nucleus that function as hubs of RNA processing. Previous translational work from our laboratory and others have shown that AD/ADRD exhibit defects in RNA processing and mislocalization of several nuclear speckle proteins including MSUT2, PABPN1, and SRRM2. We have leveraged our C. elegans model of tauopathy to begin to dissect the functional role of nuclear speckles in tau pathology. We found tau mediated neuronal dysfunction and neurodegeneration can be rescued by loss of a nuclear speckle resident E3 ubiquitin ligase adaptor protein known as SPOP. We hypothesize SPOP-mediated degradation of substrate proteins impacts the dynamics and liquid-liquid phase separation of nuclear speckles to modulate the toxicity of pathological tau. Given the high level of conservation of the nuclear speckle proteins and RNA processing system between mammals and C. elegans, we propose to utilize both C. elegans and mouse transgenic tauopathy models to dissect the molecular mechanisms by which SPOP loss of function protects against tau neurotoxicity. The Specific Aims of this project are to: 1) Define SPOP’s impact on neuronal nuclear speckle composition and dynamics in tauopathy. 2) Identify critical non-degradative CUL3SPOP E3 ligase ubiquitination substrate(s) participating in tauopathy. 3) Explore the role of critical CUL3SPOP substrate proteins in both human disease and mouse models of tauopathy. By completing the proposed work, we will develop new molecular understanding of disease mechanisms by which nuclear speckles and the SPOP protein participate in tauopathy. This work will also provide the first translational effort at understanding whether targeted changes in nuclear speckles can protect neurons from pathological tau in the mammalian brain.