Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance

精胺合酶缺乏和多胺失衡的神经毒性

基本信息

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
项目类别：
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&apos s disease model Alzheimer&apos 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

项目摘要

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.

标题：精胺合成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 博士，格林伍德遗传中心，格林伍德，南卡罗来纳州 Co-I：Luigi Bocto，医学博士，克莱姆森大学护理学院，南卡罗来纳州克莱姆森项目概要多胺，即亚精胺、精胺及其前体腐胺受到严格监管生命所必需的聚阳离子出现了，将多胺代谢与神经系统疾病联系起来。观察到伴随多种脑损伤的异常多胺水平，包括多胺代谢在缺血性脑损伤和创伤性脑损伤中发挥着关键作用。将 Snyder-Robinson 智力障碍综合症 (SRS、OMIM 309583) 的因果突变映射到精胺合成酶 (SMS)，一种催化亚精胺转化为精胺的酶。上一个资助周期（R01 NS109640）研究了多胺不平衡的病理后果 SRS 背景下的神经系统我们建立了 SRS 的果蝇模型来概括几个。 SRS 病理学的关键特征，揭示了氧化还原状态的改变、蛋白质乙酰化失调，以及溶酶体功能障碍是 SRS 病理学基础的主要神经毒性，最重要的是，已经确定苯丁酸 (PBA) 作为 SRS 体内模型和体内神经毒性的强大药理学抑制剂最近，我们令人兴奋地发现了多胺代谢之间的关键联系。具体来说，我们发现 SMS 的完全丧失会导致神经退行性变。 SRS、SMS 部分缺失（SMS+/-、携带者）显示出对 Tau 蛋白病中 Tau 诱导的神经变性的抵抗力这一发现有两个重要意义：首先，多胺可能调节 Tau 聚集毒性；其次，通过调节多胺可以延缓 Tau 病神经变性的进展我们这一更新应用的目标是建立多胺之间的机制联系。代谢和 Tau/淀粉样蛋白聚集神经毒性，并根据使用互补模型系统调节多胺代谢；1) 体内果蝇模型，2) 人类来自 SRS 患者（男性，SMS-/y）和杂合携带者（女性，SMS+/-）的成纤维细胞，以及 3）基因人类阿尔茨海默病相关痴呆 (ADRD) 数据集的表达分析。调节多胺代谢和改变精胺/亚精胺比例可增强自噬通量，调节全球乙酰化景观，促进有毒 Tau/淀粉样蛋白低聚物物种的清除，并赋予我们建议定义代谢和细胞机制。潜在的 SMS+/- 介导的神经保护作用，对抗 Tau/淀粉样蛋白积累引起的神经变性果蝇体内（目标 1）；表征 SRS 患者原代细胞的自噬流和蛋白质稳态（男性，SMS-/y）、携带者（女性，SMS-/+）和对照（+/+）（目标 2）；并进行 ADRD RNAseq 分析；和蛋白质表达数据集，以确定多胺失调的危险因素和代谢目标针对 ADRD 的神经保护（目标 3）。多胺代谢与整体蛋白质稳态之间的联系，更显着地揭示了以前尚未探索的 AD 发病机制的治疗方向。