Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance

精胺合酶缺乏和多胺失衡的神经毒性

• 批准号: 10752966
• 负责人: Rong Grace Zhai
• 金额: $ 112.85万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-14 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752966
• 关键词: Acetylation; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid; Autophagocytosis; Biochemical; Biological Models; Brain; Brain Injuries; Cells; Chemicals; Collaborations; Data Set; Doctor of Philosophy; Drosophila genus; Enzymes; Family; Female; Fibroblasts; Functional disorder; Gene Expression; Gene Expression Profiling; Genetic; Goals; Grant; Heterozygote; Human; Intervention; Ischemic Brain Injury; Legal patent; Life; Link; Lysosomes; Manuscripts; Maps; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Mutation; Nerve Degeneration; Nervous System; Neurons; Online Mendelian Inheritance In Man; Outcome; Oxidation-Reduction; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenylbutyrates; Polyamine Catabolism; Polyamines; Protein Acetylation; Putrescine; Research; Resistance; Risk Factors; Role; School Nursing; Snyder-Robinson syndrome; Spermidine; Spermine; Spermine Synthase; Tauopathies; Testing; Therapeutic; Toxic effect; Traumatic Brain Injury; Universities; Work; X-linked intellectual disability; biobank; causal variant; design; in vivo; in vivo Model; loss of function; lymphoblast; male; medical schools; metabolic profile; nervous system disorder; neurodegenerative phenotype; neuroprotection; neurotoxicity; novel; pharmacologic; polycation; protein expression; proteostasis; tau Proteins; tau aggregation; tau mutation; tissue culture; transcriptome sequencing

Title: Neurotoxicity of Spermine Synthase-Deficiency and Polyamine Imbalance PI: R. Grace Zhai, PhD, University of Miami School of Medicine, Miami, FL Co-I: Rich Steet, PhD, Greenwood Genetic Center, Greenwood, SC Co-I: Luigi Boccuto, MD, Clemson University School of Nursing, Clemson, SC PROJECT SUMMARY Polyamines, namely spermidine, spermine, and their precursor putrescine are tightly regulated polycations essential for life. First indications linking polyamine metabolism and neurological disorders came from the observations of abnormal polyamine levels accompanying several brain injury conditions including ischemic brain damage and traumatic brain injury. The pivotal role of polyamine metabolism emerged with the mapping of causal mutation of Snyder-Robinson Intellectual Disability Syndrome (SRS, OMIM 309583) to spermine synthase (SMS), an enzyme that catalyzes the conversion of spermidine to spermine. Our work in the previous grant cycle (R01 NS109640) investigated the pathological consequence of polyamine imbalance in the nervous system in the context of SRS. We have established a Drosophila model for SRS to recapitulate several key features of SRS pathology, have uncovered altered redox state, dysregulated protein acetylation, and lysosomal dysfunction as primary neurotoxicity underlying SRS pathology, and most importantly, have identified phenylbutyrate (PBA) as a robust pharmacological suppressor of neurotoxicity in SRS in vivo models and in patient cells. Recently, we made the exciting discovery of the critical connection between polyamine metabolism and Tau aggregation-induced neurodegeneration. Specifically, we found that while complete loss of SMS causes SRS, partial loss of SMS (SMS+/-, carriers) showed resistance to Tau-induced neurodegeneration in Tauopathy models. This finding has two important implications: first, polyamines may regulate Tau aggregational toxicity; and second, progression of neurodegeneration in Tauopathy could be delayed by modulating polyamine metabolism. Our objectives for this renewal application are to establish the mechanistic link between polyamine metabolism and Tau/amyloid aggregational neurotoxicity, and identify neuroprotective strategies based on modulating polyamine metabolism using complementary model systems; 1) in vivo Drosophila models, 2) human fibroblasts cells from SRS patients (male, SMS-/y) and heterozygous carriers (female, SMS+/-), and 3) gene expression analyses of human Alzheimer’s Disease related dementia (ADRD) datasets. We hypothesize that modulating polyamine metabolism and shifting spermine/spermidine ratio enhances autophagic flux, regulates global acetylation landscape, facilitates the clearance of toxic Tau/amyloid oligomer species, and confers resistance to neurodegeneration in proteinopathy. We propose to define metabolic and cellular mechanisms underlying SMS+/- mediated neuroprotection against Tau/amyloid accumulation-induced neurodegeneration in vivo in Drosophila (Aim 1); characterize autophagic flux and proteostasis in human primary cells of SRS patient (male, SMS-/y), carriers (female, SMS-/+), and controls (+/+) (Aim 2); and carry out analysis of ADRD RNAseq and protein expression datasets to identify polyamine dysregulation risk factors and metabolic targets for neuroprotection against ADRD (Aim 3). The proposed research will reveal novel chemical and molecular connection between polyamine metabolism and global protein homeostasis, and more importantly reveal a previously unexplored therapeutic direction for AD pathogenesis.

精胺合酶缺乏和多胺失衡的神经毒性 PI：R。Grace Zhai，博士，迈阿密大学医学院，佛罗里达州迈阿密 Co-I：Rich Steet，PhD，Greenwood Genetic Center，Greenwood，SC Co-I：Luigi Boccuto，医学博士，克莱姆森大学护理学院，克莱姆森，SC 项目摘要 多胺，即亚精胺，精胺，和它们的前体腐胺是严格管制的 生命所必需的聚阳离子。多胺代谢和神经系统疾病的第一个迹象是 从伴随几种脑损伤状况的异常多胺水平的观察， 缺血性脑损伤和创伤性脑损伤。多胺代谢的关键作用是随着 Snyder-Robinson智力残疾综合征（SRS，OMIM 309583）的因果突变定位， 精胺合酶（SMS），一种催化亚精胺转化为精胺的酶。我们搞好 前一个研究周期（R 01 NS 109640）研究了多胺失衡的病理后果， 在SRS的背景下神经系统。我们已经建立了一个果蝇模型SRS概括了几个 SRS病理学的关键特征，揭示了改变的氧化还原状态，失调的蛋白质乙酰化， 溶酶体功能障碍是SRS病理学基础的主要神经毒性，最重要的是， 苯丁酸（PBA）作为SRS体内模型和 患者细胞。最近，我们取得了令人兴奋的发现多胺代谢之间的关键联系 和Tau聚集诱导的神经变性。具体来说，我们发现，虽然完全丢失短信的原因， SRS，SMS的部分丢失（SMS+/-，携带者）显示出对Tau病中Tau诱导的神经变性的抵抗 模型这一发现有两个重要意义：第一，多胺可能调节Tau的聚集毒性; 第二，调节多胺可以延缓Tau病神经退行性变的进展 新陈代谢.我们的目的是为这个更新申请是建立多胺之间的机械联系， 代谢和Tau/淀粉样蛋白聚集神经毒性，并确定基于 使用互补模型系统调节多胺代谢; 1）体内果蝇模型，2）人 来自SRS患者（男性，SMS-/y）和杂合携带者（女性，SMS+/-）的成纤维细胞，和3）基因 人类阿尔茨海默病相关痴呆（ADRD）数据集的表达分析。我们假设 调节多胺代谢和改变精胺/亚精胺比率增强自噬通量，调节 全球乙酰化景观，有利于清除有毒的Tau/淀粉样蛋白寡聚体物质，并赋予 对蛋白质病中神经变性的抵抗。我们建议定义代谢和细胞机制 潜在的SMS+/-介导的针对Tau/淀粉样蛋白积累诱导的神经变性的神经保护作用 在果蝇体内（目的1）;表征SRS患者的人原代细胞中的自噬通量和蛋白质稳态 (male，SMS-/y）、携带者（女性，SMS-/+）和对照（+/+）（目的2）;并进行ADRD RNAseq分析 和蛋白质表达数据集，以确定多胺失调的风险因素和代谢目标， 针对ADRD的神经保护（目的3）。这项拟议中的研究将揭示新的化学和分子 多胺代谢和整体蛋白质稳态之间的联系，更重要的是揭示了一个 以前未探索的AD发病机制的治疗方向。