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.

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散发性疾病。 Tau蛋白病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 蛋白聚集体积累的结果神经原纤维缠结、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额颞叶痴呆的主要形式，具有与新型低效遗传相关的 tau 蛋白包涵体 VCP 突变可能与抗 tau 解聚酶活性丧失有关。然而，超形态VCP 突变会导致一种称为多系统蛋白质病的独特疾病，可表现为额颞叶病伴有 TDP-43 内含物的脑叶变性。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不同病理的机制。我们将进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 如何突变影响解聚酶活性。我们将把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，我们将确定 VCP 活性的增加或减少是否可以改变体内 tau 毒性。这些机制共同作用研究将阐明 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蛋白疗法提供基础。