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出对更多 常见的散发性疾病。焦虑症是一组致命的神经系统疾病，包括阿尔茨海默病， 痴呆和神经变性是病理性tau蛋白聚集物在 神经纤维缠结、Pick小体或神经胶质包涵体的形式。我们发现了一种新的常染色体 伴有tau包涵体的显性额颞痴呆与一种新的亚型遗传相关 VCP的突变可能与抗tau解聚酶活性的丧失有关。然而，多形性VCP 基因突变会导致一种称为多系统蛋白病的独特疾病，这种疾病可表现为额颞部 伴有TDP-43包裹体的大叶变性。我们提出了三个具体目标来理解基本分子 这种基因突变导致多种病理变化的机制。我们将进行结构生物学 更好地了解VCP蛋白如何与病理性蛋白聚集体相互作用以及VCP如何 突变会影响解聚酶的活性。我们将把这些研究扩展到细胞/神经元VCP敲入 用于确定VCP突变如何影响细胞内VCP活性的模型。最后，我们会 确定VCP活性的得失是否可以改变tau的体内毒性。总而言之，这些机械论 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， 为未来基于调节VCP活性的新型抗tau疗法提供了基础。