Sustained eIF5A hypusination at the core of brain metabolic dysfunction in TDP-43 proteinopathies

持续的 eIF5A 抑制是 TDP-43 蛋白病脑代谢功能障碍的核心

• 批准号: 10557547
• 负责人: Maj-Linda B Selenica
• 金额: $ 27.54万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557547
• 关键词: Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Amyloid; Animal Model; Astrocytes; Biochemical; Bioenergetics; Biological; Biological Assay; Biology; Brain; Brain Diseases; Brain region; Cells; Centers of Research Excellence; Clinical; Clinical Trials; Coculture Techniques; Consensus; Coupling; DNA-Binding Proteins; Data; Defect; Dementia; Disease; Elderly; Elongation Factor; Encephalopathies; Enzymes; Equilibrium; Failure; Functional disorder; Genes; Genetic; Genus Hippocampus; Glucose; Goals; Healthcare; Hemostatic function; Homeostasis; Imaging Techniques; Impaired cognition; Impairment; Knowledge; Link; Lysine; Mass Fragmentography; Measures; Metabolic; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Neuropathogenesis; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Phenotype; Prosencephalon; Proteins; Rodent; Role; Severities; Structure; Synaptic plasticity; System; Technology; Therapeutic Effect; Transgenic Mice; Virulence Factors; Work; age related; behavioral phenotyping; blood glucose regulation; brain dysfunction; brain metabolism; clinical diagnosis; cognitive performance; comorbidity; deoxyhypusine monooxygenase; deoxyhypusine synthase; diabetic; diabetic patient; eIF-5A; glucose metabolism; glucose uptake; hypusine; limbic-predominant age-related TDP-43 encephalopathy; metabolomics; mitochondrial dysfunction; mouse model; nano-string; neuropathology; novel; novel therapeutics; pharmacologic; protein TDP-43; response; tau Proteins; therapeutic biomarker; therapeutic target; transcriptomics

PROJECT SUMMARY/ ABSTRACT TAR DNA-binding protein 43 (TDP-43) pathology is associated with clinical dementia and occurs in more than half of clinically diagnosed Alzheimer’s disease (AD) patients (1, 2). The discovery of limbic-predominant TDP-43 encephalopathy (LATE) emphasized the importance of age-related TDP-43 proteinopathy, with or without co-morbid AD pathological hallmarks. The lack of disease-modifying agents against TDP-43 pathology creates an urgent need to identify novel therapeutic pathways against TDP-43 proteinopathy. Interestingly, regional disruption of glucose uptake and utilization is linked to the progression of AD neuropathology (3-5), and yet, there is no consensus on the effect of TDP-43 on glucose and energy homeostasis in the diseased brain (6). This proposal will address this significant gap in knowledge by studying the impact of the eIF5A hypusination pathway on the brain’s metabolic state in TDP-43 pathology. eIF5A is an initiation/elongation factor and the only protein undergoing hypusination (eIF5AHyp). Deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) activity convert a single lysine to a hypusine moiety. Our feasibility data finds that TDP-43 pathology in AD brain and TDP-43 mouse models induces DHS expression and hypusine levels. Additionally, we show that enhanced hypusination exacerbates TDP-43 pathology, dysregulates brain glucose homeostasis and exerts mitochondrial bioenergetic defects. Our central hypothesis states that DHS-targeted strategies reducing hypusine levels will ameliorate TDP-43 neuropathogenesis by restoring brain glucose metabolism and mitochondrial bioenergetics, upstream of cognitive decline and neurodegeneration. In Aim 1, we will establish how conditional deletion of the DHS (DHSko) in the adult forebrain of the TDP-43 transgenic mouse model will affect the brain metabolic transcriptomic profile via NanoString analysis and determine biological signatures that define the eIF5AHyp - TDP-43 phenotype. We will also utilize the CNS-Met Metabolomics Core to measure brain metabolite levels, while biochemically determining metabolic proteins, enzymes, and TDP-43 pathology. We will further elucidate how DHSko can rescue LTP, cognitive performance, and neurodegeneration associated with TDP-43 phenotype of a novel TDP-43 animal model. In Aim 2, we will define the role of eIF5AHyp on the mitochondrial bioenergetics of neurons and astrocytic-responsive neurons. We will establish how DHS inhibition rescues mitochondrial bioenergetics and restores metabolite balance in primary cells. We will also determine the cellular and mitochondrial TDP-43 accumulation and mitochondrial structure integrity. Overall, the proposed studies will provide evidence that the eIF5AHyp pathway in the TDP-43 phenotype is upstream of irreversible stages of dementia. It also offers the first detailed mechanisms of how reducing hypusine restores glucose dysregulation and mitochondrial dysfunction, maintaining neuro-astrocytic support and healthy neuronal activity, while rescuing the pathological phenotype in animal models of TDP-43 proteinopathy.

项目摘要/摘要 TAR DNA结合蛋白43（TDP-43）病理与临床痴呆相关， 超过一半的临床诊断的阿尔茨海默病（AD）患者（1，2）。边缘优势的发现 TDP-43脑病（LATE）强调了年龄相关的TDP-43蛋白病的重要性， 没有共病AD病理学特征。缺乏针对TDP-43病理学的疾病修饰剂 迫切需要鉴定针对TDP-43蛋白质病的新治疗途径。有趣的是， 葡萄糖摄取和利用的局部破坏与AD神经病理学的进展有关（3-5）， 然而，关于TDP-43对患病大脑中葡萄糖和能量稳态的影响，还没有达成共识（6）。 该提案将通过研究eIF 5A hypusination的影响来解决这一重大知识缺口 在TDP-43病理学中脑代谢状态的通路。eIF 5A是一种起始/延伸因子， 经历羟腐胺赖氨酸化的蛋白质（eIF 5AHyp）。脱氧羟腐胺赖氨酸合酶（DHS）和脱氧羟腐胺赖氨酸羟化酶 （DOHH）活性将单个赖氨酸转化为羟腐胺赖氨酸部分。我们的可行性数据发现，TDP-43病理在 AD脑和TDP-43小鼠模型诱导DHS表达和羟腐胺赖氨酸水平。此外，我们表明， 增强的羟腐胺酸中毒加重TDP-43病理，使脑葡萄糖稳态失调， 线粒体生物能量缺陷我们的中心假设指出，以DHS为目标的战略， 羟腐胺赖氨酸水平将通过恢复脑葡萄糖代谢来改善TDP-43神经发病机制， 线粒体生物能量学，认知能力下降和神经退行性变的上游。在目标1中，我们 建立TDP-43转基因小鼠成年前脑中DHS（DHSko）的条件性缺失 模型将通过NanoString分析影响大脑代谢转录组学谱，并确定生物学特性。 定义eIF 5AHyp-TDP-43表型的标签。我们还将利用CNS-Met代谢组学核心， 测量大脑代谢物水平，同时生化测定代谢蛋白质，酶和TDP-43 病理我们将进一步阐明DHSko如何拯救LTP，认知表现和神经退行性变 与新TDP-43动物模型的TDP-43表型相关。在目标2中，我们将定义eIF 5AHyp的作用 神经元和星形胶质细胞反应神经元的线粒体生物能量学。我们会确定国安局 抑制拯救线粒体生物能量学并恢复原代细胞中的代谢物平衡。我们还将 测定细胞和线粒体TDP-43积累和线粒体结构完整性。总体看 拟议的研究将提供证据表明，TDP-43表型中的eIF 5AHyp途径是 不可逆转的痴呆阶段它还提供了第一个详细的机制，如何减少羟腐胺赖氨酸恢复 葡萄糖失调和线粒体功能障碍，维持神经星形胶质细胞支持和健康的神经元 活性，同时挽救TDP-43蛋白质病动物模型中的病理表型。