Protein homeostasis in a frontotemporal dementia iPSC model

额颞叶痴呆 iPSC 模型中的蛋白质稳态

• 批准号: 10525437
• 负责人: Charleen T Chu
• 金额: $ 43.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525437
• 关键词: ATP phosphohydrolase; Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyotrophic Lateral Sclerosis; Aphasia; Autophagocytosis; Back; Biological; CRISPR/Cas technology; Cell model; Cells; Chromosomal Stability; Cyclic AMP-Dependent Protein Kinases; Destinations; Disease; Exhibits; Fibroblasts; Foundations; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; Future; Goals; Golgi Apparatus; Grant; Health; Homeostasis; Human; Inclusion Body Myopathy with Early-Onset Paget Disease; Infrastructure; Lead; Link; Mediating; Modeling; Morphology; Motor Neurons; Musculoskeletal Diseases; Mutation; Myoblasts; N Domain; NF1 gene; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurons; PINK1 gene; Parkinson Disease; Parkinsonian Disorders; Pathogenicity; Patients; Phenotype; Phosphotransferases; Play; Primary Progressive Aphasia; Process; Protein Biosynthesis; Protein Secretion; Proteins; Reagent; Role; Source; Stress; Synapses; System; Testing; Transfection; Translating; brain cell; cell type; cofactor; design; disease-causing mutation; endoplasmic reticulum stress; induced pluripotent stem cell; link protein; motor disorder; multisystem proteinopathy; novel therapeutic intervention; pluripotency; protein biomarkers; protein function; protein transport; proteostasis; valosin containing protein mutation; valosin-containing protein

Maintaining protein homeostasis is a particular challenge for neurons, in which a high demand for protein synthesis, folding and transport represents a constant source of stress. Evidence of protein mishandling is observed in nearly all neurodegenerative diseases including the AD-related dementias (ADRD). The AAA- ATPase valosin-containing protein (VCP) plays a central role in maintaining multiple aspects of protein homeostasis. Mutations in VCP have been linked to several forms of frontotemporal lobar degeneration with or without concurrent motor dysfunction and musculoskeletal disease. Yet there is limited understanding of how these mutations affect different aspects of VCP function in neurons. The VCP-T262A mutation causes familial frontotemporal dementia with aphasia and parkinsonism. Preliminary studies in primary neurons transfected with VCP-T262A reveal deficits in dendritic arborization, and patient fibroblasts bearing the endogenous mutation exhibit disrupted secretory function. Reagents to create human neurons and other relevant cell types bearing the endogenous VCP-T262A mutation are critically needed to study pathophysiological mechanisms of disease. In this exploratory project, we will create isogenic pairs of iPSC lines expressing T262A vs. wild type VCP. We will differentiate to cortical neurons to study the effects of this mutation upon ER stress, autophagy and Golgi markers compared to iPSC-derived cells with a mutation in a different VCP functional domain. Our long-range goals are to understand how alterations in VCP contribute to synaptic loss so that this mechanistic understanding can be translated into new therapeutic approaches.

对于神经元来说，维持蛋白质的动态平衡是一项特别的挑战，因为神经元对蛋白质的需求很高 合成、折叠和运输是持续的压力源。蛋白质处理不当的证据是 在几乎所有神经退行性疾病中观察到，包括阿尔茨海默病相关痴呆(ADRD)。AAA- ATPase Valosin-Holding Protein(VCP)在维持蛋白质的多个方面起着核心作用 动态平衡。VCP的突变与几种形式的额颞叶变性有关 或没有并发运动功能障碍和肌肉骨骼疾病。然而，人们对这一点的了解有限 这些突变如何影响神经元中VCP功能的不同方面。VCP-T262a突变导致 伴有失语和帕金森氏症的家族性额颞部痴呆。原代神经元的初步研究 转染VCP-T262a的患者显示树突状树枝形成缺陷，患者成纤维细胞携带 内源性突变表现为分泌功能紊乱。制造人类神经元和其他物质的试剂 携带内源性VCP-T262a突变的相关细胞类型亟需研究 疾病的病理生理机制。在这个探索性项目中，我们将创建IPSC的同源基因对 表达T262a和野生型VCP的品系。我们将分化为皮质神经元来研究这一效应 内质网应激、自噬和高尔基体标志物的突变与IPSC来源的细胞的比较 不同的VCP功能域。我们的长期目标是了解VCP的变化 有助于突触丢失，这样这种机械性的理解就可以转化为新的治疗方法 接近了。