The role of AIF3 in neurodegeneration of Alzheimer's disease

AIF3在阿尔茨海默病神经退行性疾病中的作用

• 批准号: 10626004
• 负责人: Yingfei Wang
• 金额: $ 56.94万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626004
• 关键词: APP-PS1; Acceleration; Adult; Age; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Behavior; Binding; Bioenergetics; Biology; Brain; CRISPR/Cas technology; Cell model; Cognition; Cognitive deficits; Complex; DNA Sequence Alteration; Data; Dementia; Development; Diamond; Elements; Ensure; Etiology; Event; Exons; Flavoproteins; Foundations; Free Radical Scavengers; Free Radicals; Generations; Genes; Genetic; Goals; Hippocampus; Human; Impaired cognition; Individual; Introns; Length; Life; Link; Mass Spectrum Analysis; Mediating; Memory Loss; Mitochondria; Mitochondrial Proteins; Molecular; Morphology; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Neuropathy; Nuclear; Nuclear Translocation; Pathogenesis; Phenotype; Physical condensation; Play; Production; Protein Isoforms; Proteins; RNA; RNA Splicing; Regulation; Reproducibility; Research; Research Personnel; Risk Factors; Role; Senile Plaques; Structure; Synapses; Tamoxifen; Techniques; Testing; Thinking; Untranslated RNA; Vertebral column; X Chromosome; abeta accumulation; aging brain; apoptosis inducing factor; density; drug development; effective therapy; experience; gain of function; loss of function; mRNA Precursor; mitochondrial dysfunction; mouse model; neurofibrillary tangle formation; neuron loss; new therapeutic target; novel; novel strategies; novel therapeutic intervention; overexpression; prevent; progressive neurodegeneration; replication factor C; spatial memory; success; tau Proteins; tau-1; tool; transcriptome

Project summary Alzheimer's disease (AD) is a leading cause of dementia, which is characterized by memory loss and thinking problems interfering with daily life. Although the importance of beta amyloid and Tau in AD pathogenesis has been well appreciated, unfortunately no effective treatment is available to prevent dementia progress so far due to the lack of understanding of neurodegeneration in AD, which encourages researchers in the field to further identify novel risk factors and to explore the complexity of AD pathogenesis. Recent integrative transcriptome analyses of the aging brain have revealed that aberrant alternative splicing events are reproducibly associated with AD and multiple mitochondrial proteins have been identified as new risk factors, implicating the importance of mitochondria dysfunction and pre-mRNA splicing in AD pathogenesis. Apoptosis-inducing factor (AIF) is an X-chromosome linked mitochondrial flavoprotein serving as a free radical scavenger and plays a vital function in mitochondrial bioenergetics. Spontaneous genetic mutations of AIF have been observed in both human and mouse and provided strong association of Aif gene with the etiology of neuropathy and cognitive impairment. Recently, we unexpectedly discovered a hitherto unknown AIF splicing isoform lacking two exons at its N- terminus, defined as AIF3 distinct to other two known isoforms. AIF3 was undetectable in normal human or mouse brain, but induced in human AD patients. Induction of AIF3 splicing in mouse brain caused human AD- like phenotypes, including mitochondrial dysfunction, phospho-Tau and beta amyloid aggregation, neurofibrillary tangle structure formation, and neuron loss in cortex and hippocampus. Our extensive preliminary data as well as genetic evidence provide the strong scientific premise and lead us to hypothesize that AIF3 splicing plays an essential role in neurodegeneration and AD pathogenesis. The goals of this R01 project are to 1) obtain a comprehensive understanding of AIF3 functions in cognitive deficits and neurodegeneration in AD; 2) decipher the molecular mechanisms of AIF3-meidated neurodegeneration; 3) dissect the molecular and cellular mechanisms of AIF3 splicing regulation in AD using unbiased approaches. In addition to the assembly of a strong AD research team to ensure the success of the proposed project, two tamoxifen inducible AIF3 mouse models have been established successfully in the lab, which provide valuable tools to understand the role of AIF3 in neurodegeneration in AD by gain-of-function and loss-of-function approaches. Successful completion of this project will discover significant new functions of AIF3 in AD pathogenesis, which may lead to identify a new therapeutic target for AD dementia, and also yield a valuable new mouse model for understanding AD pathogenesis and a platform for AD drug development.

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是导致痴呆的主要原因之一，其特征是记忆丧失和思维障碍 干扰日常生活的问题。尽管β淀粉样蛋白和Tau蛋白在AD发病机制中的重要性已经被证实， 然而，不幸的是，到目前为止，还没有有效的治疗方法来预防痴呆症的进展， 对AD中神经退行性变缺乏了解，这鼓励该领域的研究人员进一步研究 确定新的危险因素，并探讨AD发病机制的复杂性。最近整合转录组 对衰老大脑的分析表明，异常的选择性剪接事件可重复地与 与AD和多种线粒体蛋白已被确定为新的危险因素，暗示的重要性， 线粒体功能障碍和前体mRNA剪接在AD发病机制中的作用。凋亡诱导因子（AIF）是一种 X染色体连锁的线粒体黄素蛋白作为一种自由基清除剂， 线粒体生物能量学AIF的自发性基因突变已经在人类和哺乳动物中观察到。 Aif基因与神经病和认知障碍的病因学有很强的相关性。 最近，我们意外地发现了一种迄今未知的AIF剪接异构体，其N-端缺失两个外显子， 末端，定义为与其他两种已知同种型不同的AIF 3。AIF 3在正常人中检测不到， 小鼠脑，但在人类AD患者中诱导。小鼠脑中AIF 3剪接的诱导引起人AD-1 相似的表型，包括线粒体功能障碍、磷酸化Tau和β淀粉样蛋白聚集、神经细胞凋亡、 缠结结构形成和皮层和海马神经元丢失。我们大量的初步数据 因为遗传学证据提供了强有力的科学前提，并使我们假设AIF 3剪接起着重要作用。 在神经变性和AD发病机制中起重要作用。本R 01项目的目标是：1）获得 全面了解AIF 3在AD认知缺陷和神经退行性变中的功能; 2）破译 AIF 3介导的神经退行性变的分子机制; 3）从分子和细胞水平剖析AIF 3介导的神经退行性变的机制。 使用无偏方法研究AD中AIF 3剪接调控的机制。除了强大的组装 为确保AD研究团队提出的项目成功，两种他莫昔芬诱导的AIF 3小鼠模型 已经在实验室中成功建立，这为了解AIF 3在 通过功能获得和功能丧失的方法来评估AD中的神经变性。成功完成本 该项目将发现AIF 3在AD发病机制中的重要新功能，这可能导致识别新的 AD痴呆的治疗靶点，也为了解AD提供了一种有价值的新小鼠模型 发病机制和AD药物开发的平台。