Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance

精胺合酶缺乏与多胺失衡的神经毒性 Pi：R.Grace Zhai，博士，佛罗里达州迈阿密大学医学院 CO-I：Rich Steet，博士，格林伍德遗传中心，南卡罗来纳州格林伍德 第一名：路易吉·布洛托，医学博士，克莱姆森大学护理学院，加州大学克莱姆森 项目总结 多胺，即亚精胺、精胺及其前体腐胺受到严格控制 生命所必需的聚阳离子。第一个将多胺代谢和神经疾病联系起来的迹象出现了 根据观察到的异常多胺水平伴随着几种脑损伤情况，包括 缺血性脑损伤和创伤性脑损伤。多胺代谢的关键作用出现在 斯奈德-罗宾逊智能障碍综合征(SRS，OMIM 309583)原因突变的定位 精胺合成酶(SMS)，一种催化亚精胺转化为精胺的酶。我们在中国的工作 上一个资助周期(R01 NS109640)调查了多胺失衡在 SRS背景下的神经系统。我们已经为SRS建立了一个果蝇模型 SRS病理的主要特征是发现氧化还原状态改变，蛋白质乙酰化失调，以及 溶酶体功能障碍是SRS病理基础上的主要神经毒性，最重要的是，已经确定 苯丁酸酯(PBA)作为一种强大的药物抑制SRS体内模型和动物模型中的神经毒性 病人细胞。最近，我们有了令人兴奋的发现，多胺代谢之间的关键联系 和Tau聚集诱导的神经变性。具体地说，我们发现，虽然短信完全丢失的原因 SRS，部分Sms丢失(Sms/-，携带者)显示出对Tau诱导的神经变性的抵抗 模特们。这一发现有两个重要的意义：第一，多胺可能调节Tau的聚集毒性； 第二，调节多胺可以延缓继发性神经病的神经变性进程。 新陈代谢。我们这次更新应用的目标是建立多胺之间的机械联系 代谢和牛磺酸/淀粉样蛋白聚集性神经毒性，并基于以下因素确定神经保护策略 利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)和杂合子携带者(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。我们假设 调节多胺代谢和改变精胺/亚精胺比例增强自噬通量，调节 全球乙酰化格局，促进有毒Tau/淀粉样寡聚体物种的清除，并赋予 蛋白质病对神经退行性变的抵抗。我们建议定义新陈代谢和细胞机制 Sms/介导的神经保护机制对Tau/淀粉样蛋白蓄积诱导的神经变性的保护作用 果蝇体内(目标1)；SRS患者原代细胞自噬通量和蛋白稳定的特征 (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，以确定多胺失调风险因素和代谢目标 针对ADRD的神经保护(目标3)。这项拟议的研究将揭示新的化学和分子 多胺代谢和全球蛋白质动态平衡之间的联系，更重要的是揭示了 对于AD的发病机制，以前未探索到治疗方向。

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.