Formation and function of pathologic stress granules containing RNA-Binding Protein SFPQ in tauopathy

tau蛋白病中含有RNA结合蛋白SFPQ的病理应激颗粒的形成和功能

• 批准号: 10581946
• 负责人: ROSALIND A. SEGAL
• 金额: $ 22.25万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10581946
• 关键词: Acceleration; Affect; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease related dementia; Antigens; Area; Axon; Axonal Transport; Binding; Cause of Death; Cell Nucleus; Cells; Central Nervous System; Cytoplasm; Cytoplasmic Granules; DNA Repair; Data; Defect; Disease; Early Intervention; Early identification; Event; Future; Glutamine; Human; Image; Impairment; Interruption; Intervention; Kinesin; Lead; Learning; Liquid substance; Measures; Messenger RNA; Methods; Modeling; Molecular; Molecular Conformation; Motor; Motor Neurons; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Pathology; Persons; Pharmacologic Substance; Phase; Physical condensation; Play; Proline; Protein Splicing; RNA; RNA Splicing; RNA Transport; RNA-Binding Proteins; Research; Role; T-Lymphocyte; Tauopathies; Testing; Therapeutic; Time; Translations; Work; axonopathy; axoplasm; cell type; combat; cytotoxic; genetic approach; hyperphosphorylated tau; induced pluripotent stem cell; innovation; loss of function; mRNA Export; mutant; neuronal cell body; nucleocytoplasmic transport; pharmacologic; prevent; programs; protein aggregation; protein function; stress granule; tau Proteins; tau aggregation; tau mutation; tau-1

Project Summary/Abstract: Alzheimer’s Disease and Alzheimer’s Disease Related Disorders belong to a devastating class of neurodegenerative diseases called tauopathies, marked by pathologic aggregation of hyper-phosphorylated tau protein (phospho-tau)1. An early event in the onset of tauopathies is the formation of pathologic-stress granules (p-SGs); cytotoxic biomolecular condensates (BMCs) consisting of toxic phospho-tau oligomers and RNA- binding proteins (RBPs) T-Cell Intracellular Antigen 1 (TIA1) and Splicing Factor Proline and Glutamine Rich (SFPQ) that accumulate in the cytoplasm of neural cells2–4,8. While it is evident that p-SGs play an important role in the pathogenesis of tauopathy2,3,5,75, it is unknown how they form and how they impact homeostatic functions of the proteins they sequester. Defects in axonal transport have been established as an early event accompanying phospho-tau pathology, with conformational changes in pathologic tau leading to inhibition of anterograde axonal transport through kinesin motors32–34. Since several SG associated RBPs, including SFPQ, rely on kinesins to transport mRNAs9,10, we propose that early deficits in axonal transport lead to buildup of transport RBPs in the cytoplasm, where they aggregate, contributing to formation of p-SGs. Once sequestered in p-SGs, we predict that RBP homeostatic functions are disrupted, enhancing tau-mediated neurodegeneration. To test our model, we will use innovative methods for interrupting axonal transport in WT and P301S MAPT mutant human induced cortical neurons (iCNs) and motor neurons (iMNs). We will evaluate whether disruption of particular transport programs accelerates formation of the BMCs that are the p-SGs. To determine whether sequestration of RBP SFPQ in p-SGs disrupts critical homeostatic functions in the nucleus and/or the axons of cortical and motor neurons, we will again use WT and P301S MAPT mutant human induced cortical neurons (iCNs) and motor neurons (iMNs) and interrogate the multiple essential functions of SFPQ57, including DNA repair, nuclear mRNA export, and axonal mRNA transport. Results from these studies will identify early targets for pharmacologic intervention in the pathogenesis of tauopathy and identify essential differences in the onset of disease in different cells types of the central nervous system.

项目概要/摘要： 阿尔茨海默病和阿尔茨海默病相关疾病属于一类破坏性的疾病， 称为tau蛋白病的神经退行性疾病，以过度磷酸化的tau蛋白的病理性聚集为特征 蛋白质（磷酸-tau）1. tau蛋白病发作的早期事件是病理性应激颗粒的形成 （p-SGs）;由毒性磷酸-tau寡聚体和RNA-tau寡聚体组成的细胞毒性生物分子缩合物（BMC）。 结合蛋白（RBP）T细胞胞内抗原1（TIA 1）和剪接因子脯氨酸和谷氨酰胺丰富 （SFPQ），其在神经细胞的细胞质中积累2 - 4，8。虽然很明显p-SGs发挥着重要作用， 在tau蛋白病的发病机制中，尚不清楚它们是如何形成的，以及它们如何影响稳态功能 蛋白质的含量。轴突运输缺陷已被确定为早期事件 伴随磷酸化tau病理学，病理性tau的构象变化导致抑制 通过驱动蛋白马达的顺行轴突运输32 -34.由于包括SFPQ在内的几个SG相关RBP， 依赖于驱动蛋白运输mRNA 9，10，我们提出，轴突运输的早期缺陷导致的积累， 在细胞质中转运RBP，在那里它们聚集，有助于形成p-SG。一旦被隔离 在p-SGs中，我们预测RBP稳态功能被破坏，增强tau介导的神经变性。 为了测试我们的模型，我们将在WT和P301 S MAPT中使用创新的方法来中断轴突运输。 突变的人诱导皮层神经元（iCN）和运动神经元（iMN）。我们将评估是否中断 特定的运输程序加速了作为p-SG的BMC的形成。以确定是否 RBP SFPQ在p-SG中的隔离破坏了神经元细胞核和/或轴突中的关键稳态功能。 皮质和运动神经元，我们将再次使用WT和P301 S MAPT突变体人诱导的皮质神经元 （iCN）和运动神经元（iMN），并询问SFPQ 57的多种基本功能，包括DNA 修复、核mRNA输出和轴突mRNA运输。这些研究的结果将确定早期目标 用于tau蛋白病发病机制的药物干预，并确定tau蛋白病发病的本质差异。 中枢神经系统的不同细胞类型的疾病。