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.

维持蛋白质稳态是对神经元的特殊挑战，在该神经元中，对蛋白质的需求很高 合成，折叠和运输代表恒定的应力来源。蛋白质不当的证据是 在几乎所有神经退行性疾病中都观察到，包括与AD相关的痴呆症（ADRD）。 AAA- 含ATPase Valosin的蛋白质（VCP）在维持蛋白质的多个方面起着核心作用 稳态。 VCP中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，对 这些突变如何影响神经元中VCP功能的不同方面。 VCP-T262A突变原因 家庭性额颞痴呆症患有失语和帕金森氏症。初级神经元的初步研究 用VCP-T262A转染的揭示了树突状树皮的缺陷，患者成纤维细胞带有携带 内源性突变表现出破坏的分泌功能。创建人类神经元和其他人的试剂 具有内源性VCP-T262A突变的相关细胞类型需要研究 疾病的病理生理机制。在这个探索性项目中，我们将创建IPSC的异源对 表达T262A与野生型VCP的线。我们将与皮质神经元区分开来研究这一点的影响 与IPSC衍生的细胞相比，ER应力，自噬和高尔基体标记物具有突变的突变 不同的VCP功能域。我们的远程目标是了解VCP的变化如何 有助于突触损失，以便将这种机械理解转化为新的治疗 方法。