Loss of VCP Function in Frontotemporal Lobar Degeneration

额颞叶变性导致 VCP 功能丧失

• 批准号: 10440933
• 负责人: Edward Byung-Ha Lee
• 金额: $ 235.61万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440933
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; ATPase Domain; Affect; Alleles; Alzheimer' s Disease; Biochemistry; Biological; Brain Diseases; Cell model; Cells; Complex; Cryoelectron Microscopy; DNA Sequence Alteration; Dementia; Deposition; Disease; Exhibits; Foundations; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; Future; Gene Mutation; Genes; Genetic; Goals; Heterogeneity; Impairment; Inclusion Body Myositis; Knock-in; Knock-in Mouse; Lead; Link; Maps; Methods; Modeling; Molecular; Molecular Abnormality; Mutation; N-terminal; Names; Neocortex; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear; Osteitis Deformans; Pathologic; Pathology; Pharmacology; Phenotype; Pick body; Polyubiquitin; Protein Inhibition; Proteins; Rare Diseases; Structure; Tauopathies; Testing; Toxic effect; Transgenic Mice; Vacuole; base; clinical phenotype; human disease; in vitro activity; in vivo; insight; mouse model; multisystem proteinopathy; mutant; nervous system disorder; neurobehavioral; neuropathology; neurotoxicity; novel; protein TDP-43; protein aggregation; protein complex; protein expression; protein function; restoration; structural biology; tau Proteins; tau aggregation; trafficking; valosin containing protein mutation; valosin-containing protein

Rare genetic causes of human disease have the potential to reveal mechanistic insights into more common sporadic disease. Tauopathies are a group of fatal neurologic diseases, including Alzheimer's disease, where dementia and neurodegeneration are the result of accumulation of pathologic tau protein aggregates in the form of neurofibrillary tangles, Pick bodies, or glial inclusions. We have identified a novel autosomal dominant form of frontotemporal dementia with tau inclusions associated with a novel hypomorphic genetic mutation in VCP which may be linked to a loss of anti-tau disaggregase activity. However, hypermorphic VCP mutations cause a distinct disease called multisystem proteinopathy which can manifest as frontotemporal lobar degeneration with TDP-43 inclusions. We propose three specific aims to understand the basic molecular mechanisms by which this gene mutation leads to diverse pathologies. We will perform structural biology studies to better understand how VCP protein interacts with pathologic protein aggregates, and how VCP mutations affect disaggregase activity. We will extend these studies into cellular/neuronal VCP knock-in models to determine how VCP mutations affect cellular VCP activity within a cellular context. Finally, we will determine whether gains or losses of VCP activity can modify tau toxicity in vivo. Together, these mechanistic studies will elucidate basic mechanisms by which VCP dysfunction leads to different types of proteinopathy, providing the basis for future novel anti-tau therapies based on modulating VCP activity.

人类疾病的罕见遗传原因有可能揭示更多的机制见解 常见的散发性疾病。Tauopathies是一组致命的神经系统疾病，包括阿尔茨海默病， 其中痴呆和神经变性是病理性tau蛋白聚集体在脑中积累的结果， 神经纤维缠结、匹克体或神经胶质内含物的形式。我们发现了一种新的常染色体 一种与一种新的亚形态遗传相关的伴有tau蛋白夹杂物的额颞叶痴呆的显性形式 VCP中的突变，其可能与抗tau解聚酶活性的丧失有关。然而，超形态VCP 突变导致一种称为多系统蛋白质病的独特疾病， 肺叶变性伴TDP-43包涵体。我们提出了三个具体的目标，以了解基本的分子 这种基因突变导致不同病理的机制。我们将进行结构生物学 研究旨在更好地了解VCP蛋白如何与病理性蛋白质聚集体相互作用以及VCP如何 突变影响解聚酶活性。我们将这些研究扩展到细胞/神经元VCP敲入 模型来确定VCP突变如何影响细胞背景下的细胞VCP活性。最后我们将 确定VCP活性的获得或丧失是否可以改变体内tau毒性。这些机械性加在一起 研究将阐明VCP功能障碍导致不同类型蛋白质病的基本机制， 为基于调节VCP活性的未来新型抗tau疗法提供基础。