Loss of VCP Function in Frontotemporal Lobar Degeneration

额颞叶变性导致 VCP 功能丧失

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

罕见的人类疾病遗传原因有可能揭示机械洞察力常见的零星疾病。陶氏病是一组致命的神经系统疾病，包括阿尔茨海默氏病，其中痴呆和神经退行性是病理tau蛋白聚集物积累的结果神经原纤维缠结，拾取身体或神经胶质包含的形式。我们已经确定了一种新颖的常染色体额颞痴呆的主要形式，带有与新型肌遗传有关的tau包含物 VCP中的突变可能与抗TAU分解酶活性的丧失有关。但是，超态VCP 突变引起一种称为多系统蛋白质病的独特疾病，可以表现为额颞带有TDP-43夹杂物的Lobar变性。我们提出了三个特定的目标，以了解基本分子该基因突变导致多种病理的机制。我们将执行结构生物学研究以更好地了解VCP蛋白如何与病理蛋白聚集体相互作用以及VCP如何相互作用突变会影响分解酶活性。我们将将这些研究扩展到细胞/神经元VCP敲入确定VCP突变如何影响细胞环境中细胞VCP活性的模型。最后，我们会的确定VCP活性的收益或损失是否可以改变体内TAU毒性。在一起，这些机械研究将阐明VCP功能障碍导致不同类型的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。