UNDERSTANDING THE ROLE OF TM2D FAMILY GENES IN NOTCH SIGNALING AND ALZHEIMER'S DISEASE

了解 TM2D 家族基因在 Notch 信号传导和阿尔茨海默病中的作用

• 批准号: 10181973
• 负责人: Shinya Yamamoto
• 金额: $ 120.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10181973
• 关键词: Adult; Affect; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein Precursor; Animal Model; Behavioral; Biochemical; Biological; Biological Assay; Biological Models; Brain; Cells; Charge; Collaborations; Complex; Data; Defect; Development; Disease; Dominant-Negative Mutation; Drosophila genus; Drosophila melanogaster; Electrophysiology (science); Embryo; Embryonic Development; Environmental Risk Factor; Enzymes; Epigenetic Process; Exhibits; Extracellular Domain; Family member; Female; Foundations; Gene Family; Gene Proteins; Genes; Genetic; Genetic Epistasis; Genomics; Heart; Human; Human Amyloid Precursor Protein; Invertebrates; Knock-out; Late Onset Alzheimer Disease; Link; Longevity; Maintenance; Mammals; Mediating; Membrane Proteins; Methodology; Methods; Molecular; Motor; Mus; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Odds Ratio; Other Genetics; Pathogenesis; Pathway interactions; Patients; Pattern; Peptides; Phenocopy; Phenotype; Play; Presenile Alzheimer Dementia; Process; Protein Family; Protein Precursors; Proteins; Proteolysis; Reporter; Reporting; Research; Research Infrastructure; Risk; Risk Factors; Role; Signal Transduction; Testing; Therapeutic Intervention; Tissues; Variant; Vertebrates; age related; amyloid precursor protein processing; base; cell type; cohort; experimental study; fly; gamma secretase; gene function; genetic risk factor; genetic variant; genomic epidemiology; in vivo; insight; loss of function; mutant; neurodegenerative phenotype; neurotoxic; new therapeutic target; notch protein; novel; overexpression; protein expression; rare variant; relating to nervous system

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a multifactorial and complex neurodegenerative disorder that involves numerous genetic, epigenetic and environmental factors. Advances in genomics have identified new genes and rare variants that are associated with AD. However, the molecular mechanisms of how these factors contribute to AD pathogenesis are largely undefined. In collaboration with the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium, we recently identified a rare missense variant in TM2D3 that is associated with a significant increase in the risk of late-onset AD (LOAD). Furthermore, a recent study by an independent group reported that another rare missense variant was found in a patient with early-onset AD. Although the function of this gene has not been explored in vertebrates in vivo, our experiments using fruit flies, Drosophila melanogaster, suggests that this gene is a potential regulator of a key enzyme that process APP, a precursor protein that produces neurotoxic Ab42 peptides that contribute to AD. In this proposal, we elucidate the molecular function of TM2D3 and its related family members (TM2D1/2) to understand their role in APP processing and AD pathogenesis using Drosophila. Flies are excellent model organisms to genetically dissect molecular mechanisms of neurodegeneration. Moreover, since APP is processed by the same set of enzymes that activate Notch, a pathway affected in TM2D3 mutant flies, rich research infrastructure for Notch signaling studies in Drosophila greatly facilitates the mechanistic study of this protein in vivo. By combining genetic, cell biological, biochemical, electrophysiological and behavioral methodologies, we will uncover how TM2D3 and its relatives modulate proteolysis of membrane proteins to understand how rare missense variants in this gene affects the risk of LOAD and EOAD in humans. Such understanding will provide novel insights into AD pathogenesis and will deliver a new framework to understand how genetic risk factors of AD may impinge on a common molecular pathway to facilitate disease expression and progression.

项目摘要/摘要 阿尔茨海默病(AD)是一种多因素和复杂的神经退行性疾病，涉及 众多的遗传、表观遗传和环境因素。基因组学的进展发现了新的 与阿尔茨海默病相关的基因和罕见的变异。然而，这些的分子机制如何 阿尔茨海默病的发病因素在很大程度上是未知的。与控方合作 (基因组流行病学中的心脏和衰老研究队列)联盟，我们最近确定了一个 罕见的TM2D3错义变异与晚发风险显著增加相关 AD(加载)。此外，一个独立组织最近的一项研究报告说，另一个罕见的误解是 在1例早发性阿尔茨海默病患者中发现突变。虽然这个基因的功能还没有被 在活体脊椎动物中进行了探索，我们使用果蝇进行的实验表明， 这个基因是处理APP的关键酶的潜在调节者，APP是一种前体蛋白， 产生对AD有贡献的神经毒性AB42多肽。在这个提议中，我们阐明了分子 TM2D3及其相关家族成员(TM2D1/2)的功能，了解它们在APP中的作用 果蝇加工与AD发病机制的研究。苍蝇是极好的遗传模式生物 剖析神经退行性变的分子机制。此外，由于APP由相同的 一组激活Notch的酶，Notch是影响TM2D3突变果蝇的一种途径，丰富的研究 果蝇Notch信号研究的基础设施极大地促进了这一机制的研究 体内的蛋白质。通过结合遗传学、细胞生物学、生化、电生理学和行为学 方法，我们将揭示TM2D3及其类似物是如何调控膜蛋白分解的 蛋白质以了解该基因中罕见的错义变异如何影响负荷和Eoad的风险 人类。这样的理解将为AD的发病机制提供新的见解，并将提供新的 理解阿尔茨海默病遗传风险因素如何影响常见分子途径的框架 以促进疾病的表达和进展。