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: 10434704
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434704
• 关键词: APP-PS1; 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 (Brain); Human; Impaired cognition; Individual; Introns; Lead; 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; 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 阿尔茨海默氏病（AD）是痴呆的主要原因，其特征是记忆力丧失和思维 干扰日常生活的问题。尽管β-淀粉样蛋白和tau在AD发病机理中的重要性具有 非常感谢，不幸的是，没有有效的治疗方法可以防止痴呆症的进展 由于缺乏对AD中神经退行性的了解，这鼓励该领域的研究人员进一步 确定新的危险因素并探索AD发病机理的复杂性。最近的集成转录组 对大脑衰老的分析表明，异常的替代剪接事件是可重复相关的 AD和多个线粒体蛋白已被确定为新的风险因素，这意味着重要性 在AD发病机理中的线粒体功能障碍和前MRNA剪接的膜片。凋亡诱导因子（AIF）是 X染色体链接的线粒体黄蛋蛋白是自由基清除剂，在 线粒体生物能学。在人类和 小鼠并提供了AIF基因与神经病和认知障碍的病因的牢固关联。 最近，我们意外地发现了一个迄今未知的AIF剪接同工型，其N-缺少两个外显子 末端定义为与其他两个已知同工型不同的AIF3。 AIF3在正常人或 小鼠大脑，但在人类广告患者中诱导。诱导小鼠大脑中AIF3剪接引起人类ad- 像表型一样，包括线粒体功能障碍，磷酸-TAU和β淀粉样蛋白聚集，神经纤维纤维 缠结结构的形成和皮质和海马的神经元丧失。我们广泛的初步数据 由于遗传证据提供了强大的科学前提，并使我们假设AIF3剪接发挥 在神经退行性和AD发病机理中的重要作用。该R01项目的目标是1） 对AD的认知缺陷和神经变性中AIF3功能的全面理解； 2）破译 AIF3杀手的神经变性的分子机制； 3）剖析分子和细胞 AIF3剪接调节在AD中使用无偏的方法的机理。除了组装强 广告研究团队确保拟议项目的成功，两个他莫昔芬诱导AIF3鼠标模型 在实验室中成功建立了，该实验室提供了有价值的工具来了解AIF3在 通过功能获得和功能丧失方法，AD中的神经变性方法。成功完成 项目将发现AIF3在AD发病机理中的重要新功能，这可能导致确定新的 AD痴呆的治疗靶标，还产生了有价值的新鼠标模型来理解AD 发病机理和AD药物开发的平台。