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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos 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

项目摘要

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/摘要焦油DNA结合蛋白43（TDP-43）病理学与临床痴呆有关，并且发生在更多一半的临床诊断为阿尔茨海默氏病（AD）患者（1，2）。边缘统治的发现 TDP-43脑病（晚）强调了与年龄相关的TDP-43蛋白质病的重要性，没有联合性广告病理标志。缺乏针对TDP-43病理的疾病调整剂迫切需要鉴定针对TDP-43蛋白质病的新型热途径。有趣的是，葡萄糖摄取和利用的区域破坏与AD神经病理学的进展有关（3-5）和然而，关于TDP-43对患病大脑中葡萄糖和能量稳态的影响尚无共识（6）。该建议将通过研究EIF5A的影响来解决这一重大差距 TDP-43病理学中大脑代谢状态的途径。 EIF5A是一个倡议/伸长因素，也是唯一的蛋白质受到非偶然（EIF5AHYP）。脱氧蛋白酶合酶（DHS）和脱氧蛋白酶羟化酶（DOHH）活性将单个赖氨酸转化为非属性部分。我们的可行性数据发现TDP-43病理 AD脑和TDP-43小鼠模型会影响DHS表达和降低水平。此外，我们表明增强的无偶然性加剧了TDP-43病理学，使脑葡萄糖稳态和运动失调线粒体生物能缺陷。我们的中心假设指出，以DHS为目标的策略减少了降低水平将通过恢复脑葡萄糖代谢和线粒体生物能学，认知下降和神经退行性的上游。在AIM 1中，我们将确定如何在TDP-43转基因小鼠的成年前脑中DHS（DHSKO）的条件缺失模型将通过纳米结构分析影响大脑代谢转录组谱并确定生物学定义EIF5AHYP -TDP -43表型的签名。我们还将利用CNS-MET代谢组学核心测量脑代谢物水平，而生物化学确定代谢蛋白，酶和TDP-43 病理。我们将进一步阐明DHSKO如何挽救LTP，认知性能和神经变性与新型TDP-43动物模型的TDP-43表型相关。在AIM 2中，我们将定义EIF5AHYP的作用在神经元和星形胶质响应神经元的线粒体生物能学上。我们将建立DHS 抑制作用反应线粒体生物能，并恢复原代细胞中的代谢物平衡。我们也会确定细胞和线粒体TDP-43积累和线粒体结构完整性。总体而言，拟议的研究将提供证据表明TDP-43表型中的EIF5AHYP途径是痴呆症的不可逆转阶段。它还提供了第一个详细的机制，即如何减少降低恢复方式葡萄糖失调和线粒体功能障碍，维持神经胃细胞支持和健康的神经元在TDP-43蛋白质病动物模型中挽救病理表型的同时。