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: 10190767
• 负责人: Yingfei Wang
• 金额: $ 56.9万
• 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/10190767
• 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.

项目总结 阿尔茨海默病(AD)是导致痴呆症的主要原因之一，其特征是记忆力和思维能力丧失 干扰日常生活的问题。尽管β淀粉样蛋白和Tau在AD发病机制中的重要性 非常感谢，不幸的是，到目前为止还没有有效的治疗方法来防止痴呆症的进展 由于缺乏对阿尔茨海默病神经变性的了解，这鼓励该领域的研究人员进一步 识别新的危险因素，探索AD发病机制的复杂性。最新整合转录组 对老化大脑的分析表明，异常的选择性剪接事件与重复相关 与AD和多种线粒体蛋白已被确定为新的危险因素，暗示了重要性 线粒体功能障碍和前-mRNA剪接在AD发病机制中的作用。细胞凋亡诱导因子(AIF)是一种 X染色体连锁的线粒体黄素蛋白作为自由基清除剂在体内发挥重要作用 线粒体生物能量学。在人类和人类中都观察到AIF的自发基因突变 并提供了AIF基因与神经病和认知障碍的病因之间的强烈关联。 最近，我们意外地发现了一个迄今未知的AIF剪接异构体，其N-端没有两个外显子。 末端，定义为AIF3，与其他两种已知的异构体不同。AIF3在正常人体内检测不到 小鼠脑内，但在人类AD患者中诱导。人阿尔茨海默病引起的小鼠脑内AIF3剪接诱导 类似的表型，包括线粒体功能障碍，磷酸化Tau和β淀粉样蛋白聚集，神经原纤维 大脑皮层和海马区结构紊乱，神经元丢失。我们广泛的初步数据也是如此 因为遗传证据提供了强有力的科学前提，并引导我们假设AIF3剪接发挥着 在神经退行性变和阿尔茨海默病发病机制中起重要作用。此R01项目的目标是：1)获得 全面了解AIF3在阿尔茨海默病认知障碍和神经退行性变中的作用；2)解密 AIF3介导的神经退行性变的分子机制；3)分子和细胞解剖 使用无偏倚方法研究AD中AIF3剪接调控的机制。除了聚集了一支强大的 AD研究团队确保拟议项目的成功，两只三苯氧胺可诱导的AIF3小鼠模型 已经在实验室中成功地建立了AIF3，这为理解AIF3在 阿尔茨海默病的神经退行性变：功能获得和功能丧失。成功完成这项工作 该项目将发现AIF3在AD发病机制中的重要新功能，这可能导致发现一种新的 AD痴呆的治疗靶点，也为理解AD提供了一个有价值的新的小鼠模型 发病机制和AD药物开发的平台。