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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos 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

项目摘要

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.

项目概要阿尔茨海默病 (AD) 是痴呆症的主要原因，其特点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已被证实遗憾的是，迄今为止，尚无有效的治疗方法可以预防痴呆症的进展由于缺乏对 AD 神经退行性变的了解，这鼓励该领域的研究人员进一步研究识别新的危险因素并探索 AD 发病机制的复杂性。最近的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是可重复相关的 AD 和多种线粒体蛋白已被确定为新的危险因素，这表明了其重要性 AD 发病机制中线粒体功能障碍和前 mRNA 剪接的研究。细胞凋亡诱导因子（AIF）是一种 X 染色体连接的线粒体黄素蛋白作为自由基清除剂，在线粒体生物能量学。在人类和人类中都观察到了 AIF 的自发基因突变小鼠并提供了 Aif 基因与神经病和认知障碍病因的密切关联。最近，我们意外地发现了一种迄今为止未知的AIF剪接亚型，其N-位缺少两个外显子。末端，定义为 AIF3，与其他两种已知亚型不同。 AIF3 在正常人或小鼠大脑，但在人类 AD 患者中诱导。小鼠大脑中 AIF3 剪接的诱导导致人类 AD- 类似表型，包括线粒体功能障碍、磷酸化 Tau 和 β 淀粉样蛋白聚集、神经原纤维缠结结构的形成以及皮质和海马体中神经元的损失。我们还有大量的初步数据因为遗传证据提供了强有力的科学前提并使我们假设 AIF3 剪接在在神经退行性变和 AD 发病机制中发挥重要作用。该 R01 项目的目标是 1) 获得全面了解 AIF3 在 AD 认知缺陷和神经退行性疾病中的功能； 2) 破译 AIF3介导的神经变性的分子机制； 3）剖析分子和细胞使用公正的方法研究 AD 中 AIF3 剪接调节的机制。除了集结强大的 AD研究团队确保所提出项目的成功，两个他莫昔芬诱导AIF3小鼠模型已在实验室成功建立，为理解 AIF3 在通过功能获得和功能丧失方法治疗 AD 中的神经变性。顺利完成本次项目将发现 AIF3 在 AD 发病机制中的重要新功能，这可能导致识别新的 AD 痴呆症的治疗靶点，并为了解 AD 提供了一个有价值的新小鼠模型 AD 发病机制和 AD 药物开发平台。