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：精子缺乏和多胺失衡的神经毒性 PI：R。GraceZhai，迈阿密大学医学院，迈阿密，佛罗里达州 Co-I：Rich Steet，PhD，Greenwood遗传中心，格林伍德，南卡罗来纳州 Co-I：Clemson大学护理学院医学博士Luigi Boccuto，SC Clemson，SC 项目摘要多胺，即精子，精子及其前体perrescine受到严格调节多阳性对生命必不可少。将多胺代谢和神经系统疾病联系起来的第一个迹象来了从观察到的异常多胺水平，经历了几种脑损伤状况缺血性脑损伤和脑部外伤。多胺代谢的关键作用与 Snyder-Robinson智障综合征（SRS，OMIM 309583）的因果突变图精子合酶（SMS），一种酶，可催化亚精胺向精子的转化。我们在以前的赠款周期（R01 NS109640）研究了多胺失衡的病理后果神经系统在SRS的背景下。我们已经建立了一个果蝇模型，以概括几个 SRS病理学的关键特征，发现了氧化还原状态的改变，蛋白质乙酰化失调，并且溶酶体功能障碍是SRS病理学基础的主要神经毒性，最重要的是已经鉴定苯基丁酸（PBA）作为体内模型中SRS和IN中神经毒性的强大药物抑制剂患者细胞。最近，我们令人兴奋地发现了多胺代谢之间的关键联系和tau聚集诱导的神经退行性。具体来说，我们发现虽然完全丢失了SMS原因 SRS，SMS的部分丢失（SMS +/-，载体）显示出对Tau诱导的Tauopathy神经退行性的抗性型号。这一发现具有两个重要的含义：首先，多胺可能调节tau的聚集毒性；其次，可以通过调节多胺来延迟神经退行性的进展代谢。我们对此更新应用的目标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，并基于基于神经保护策略使用完成模型系统调节多胺代谢； 1）体内果蝇模型，2）人类成纤维细胞来自SRS患者（雄性，SMS-/Y）和杂合载体（雌性，SMS +/-）和3）基因的细胞人类阿尔茨海默氏病有关的痴呆（ADRD）数据集的表达分析。我们假设这一点调节多胺代谢和移动的精子/精子比增强自噬通量，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，并供认蛋白质病中神经退行性的抗性。我们建议定义代谢和细胞机制潜在的SMS +/-针对TAU/淀粉样蛋白积累诱导的神经变性的神经保护作用果蝇中的体内（AIM 1）；表征SRS患者人类原代细胞中的自噬通量和蛋白抑制剂（雄性，SMS-/Y），载体（女性，SMS - /+）和控件（+/+）（AIM 2）;并进行ADRD RNASEQ的分析和蛋白质表达数据集，以识别多胺失调危险因素和代谢靶标的针对ADRD的神经保护作用（AIM 3）。拟议的研究将揭示新的化学和分子多胺代谢与全球蛋白稳态之间的联系，更重要的是揭示以前针对AD发病机理的意外治疗方向。