SPOP drives neurodegenerative tauopathy

SPOP 驱动神经退行性 tau 病

• 批准号: 10734807
• 负责人: Brian C. Kraemer
• 金额: $ 182.34万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734807
• 关键词: Adaptor Signaling Protein; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Automobile Driving; Autopsy; Brain; Caenorhabditis elegans; Cell Nucleus; Cell model; Cells; Cessation of life; Complex; Cytoplasm; Defect; Dementia; Deposition; Diagnostic; Disease; Disease model; Environment; Exhibits; Failure; Frontotemporal Lobar Degenerations; Functional disorder; Future; Genes; Genetic Screening; Goals; Human; Laboratories; Liquid substance; Mammals; Mediating; Membrane; Messenger RNA; Modeling; Molecular; Molecular Genetics; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Nuclear; Organelles; Pathologic; Pathology; Phase; Phenotype; Process; Progressive Supranuclear Palsy; Property; Proteins; RNA; RNA Processing; Resistance; Role; Scaffolding Protein; Specimen; System; Tauopathies; Testing; Toxic effect; Transgenic Mice; Transgenic Model; Transgenic Organisms; Ubiquitination; Work; biophysical properties; brain tissue; cullin-3; effective therapy; genetic analysis; genome-wide; human disease; hyperphosphorylated tau; insight; loss of function; loss of function mutation; mouse model; mutant; neuroprotection; neurotoxicity; permissiveness; premature; protein function; recruit; scaffold; tau Proteins; tau aggregation; translational potential; translational study; ubiquitin ligase; ubiquitin-protein ligase

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.

摘要： 聚集的病理tau蛋白构成阿尔茨海默病(AD)的诊断标志之一， 相关障碍(ADRD)。病理性tau导致功能障碍的分子机制 神经元的退化仍然不完全清楚。然而，病理性tau驱动的神经元 功能障碍和神经退化显然会导致痴呆症。研究病理性tau是如何导致 AD和ADRD的神经退变，我们在线虫中建立了神经退行性变的转基因模型 由人类tau聚集物驱动。在我们之前的工作中，我们发现了几个控制tau毒性的基因。 线虫包括Sut-1、Sut-2、Parn-2、Sut-6、Aly-1、Aly-2和Aly-3；所有这些基因都有共同的 编码驻留在核斑点内的蛋白质的特性。核斑点是无膜细胞器。 在细胞的细胞核内，作为RNA处理的中心。我们之前的翻译工作 实验室和其他研究表明，AD/ADRD在RNA加工中表现出缺陷和错误的定位 几种核斑点蛋白包括MSUT2、PABPN1和SRRM2。我们已经利用我们的线虫 开始解剖核斑点在tau病理中的功能作用。我们找到了陶 介导的神经元功能障碍和神经变性可以通过失去核斑点驻留的E3来挽救 泛素连接酶连接蛋白，简称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其毒性 病态的牛磺酸。鉴于核斑点蛋白和RNA加工的高度保守 哺乳动物和线虫之间的系统，我们建议同时利用线虫和小鼠的转基因。 肌病模型剖析SPOP功能丧失保护tau的分子机制 神经毒性。该项目的具体目标是：1)确定SPOP对神经元核团的影响 直立性针灸的散斑成分和动力学。2)鉴定关键的非降解CUL3SPOP E3连接酶 泛素化底物(S)参与牛顿疗法。3)探索临界CUL3SPOP底物的作用 人类疾病和小鼠肌萎缩症模型中的蛋白质。通过完成拟议的工作，我们 将发展对核斑点和SPOP疾病机制的新的分子理解 蛋白质参与伸展疗法。这项工作还将提供第一个翻译努力，以了解 核斑点的靶向变化可以保护哺乳动物大脑中的神经元免受病理性tau的影响。