The role of Selenoprotein I in mitigating neurodegeneration.

硒蛋白 I 在减轻神经退行性变中的作用。

• 批准号: 10725097
• 负责人: Peter R Hoffmann
• 金额: $ 43.04万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725097
• 关键词: Affect; Antioxidants; Apoptosis; Ataxia; Behavior; Behavioral; Biochemistry; Brain; Brain region; CDP ethanolamine; Cells; Cellular Membrane; Central Nervous System; Cessation of life; Congenital neurologic anomalies; Data; Development; Dietary Selenium; Embryo; Endoplasmic Reticulum; Enzymes; Ethanolamines; Family; Fibroblasts; Future; Generations; Genes; Gliosis; Glycerol; Goals; Hereditary Spastic Paraplegia; Homeostasis; Human; Impaired cognition; Impairment; In Vitro; Iron; Knock-out; Knowledge; Lead; Life; Lipid Peroxidation; Lipids; Lower Extremity; Measures; Mediating; Mediator; Membrane; Metabolism; Motor; Motor Neurons; Mus; Mutation; Nature; Nerve Degeneration; Neurobiology; Neurologic Deficit; Neurons; Oligodendroglia; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Phosphatidylethanolamine; Phospholipids; Plasmalogens; Play; Polyunsaturated Fatty Acids; Positioning Attribute; Predisposition; Principal Investigator; Proteins; Reaction; Reactive Oxygen Species; Reporting; Research; Role; Sampling; Seizures; Selenium; Selenocysteine; Signal Transduction; Subgroup; Transferase; Translations; Vertebral column; Work; cell type; cerebral atrophy; design; experimental study; functional disability; insight; loss of function; loss of function mutation; member; mouse model; myelination; nervous system development; neurobehavioral test; neurodevelopment; neuropathology; novel; oxidation; peroxidation; phosphoethanolamine; prevent; programs; selenoenzyme; selenoprotein; spasticity; vinyl ether; white matter

Selenoprotein I (SELENOI) is a poorly characterized enzyme that depends on adequate dietary selenium for expression and has been shown to catalyze the final reaction of the CDP-ethanolamine branch of the Kennedy pathway within the endoplasmic reticulum membrane. These pathways depend on SELENOI for efficient synthesis of phosphatidylethanolamine (PE) and plasmenyl PE, which are important phospholipids in cellular membranes. Although present in various cell-types throughout the body, PE and plasmenyl PE are particularly enriched in central nervous system (CNS), where they comprise 45% of total membrane phospholipids. Plasmenyl PE is the predominant ethanolamine phospholipid in brain, with highest levels detected in white matter, and contains a vinyl ether bond in the sn-1 position that is preferentially targeted by reactive oxygen species. In this manner, plasmenyl PE acts as an important antioxidant by preventing the peroxidation of polyunsaturated fatty acids in membrane phospholipids that can trigger ferroptosis (peroxidated diacyl PE is a particularly effective executioner of ferroptosis). In humans, rare mutations in SELENOI lead to hereditary spastic paraplegia (HSP), a neurodegenerative condition affecting upper motor neurons characterized by impaired functionality of the lower limbs. The current understanding of the mechanisms governing PE/plasmenyl PE metabolism in brain is limited, in large part due to a lack of representative mouse models that allow mechanistic studies to be conducted. Our Multiple Principal Investigator (MPI)-led research team has developed a unique mouse model for mechanistic studies that will utilize our expertise in selenoprotein biochemistry and neurobiology to generate fundamental new knowledge about SELENOI function in the CNS. In particular, we have developed a unique mouse model in which SELENOI deletion is restricted to the CNS, thereby circumventing the embryonic lethality caused by constitutive SELENOI KO in mice. Our preliminary studies have revealed striking behavioral deficits that parallel those reported in humans with rare loss-of- function SELENOI mutations. This project will address the following specific aims: 1) Identify and characterize the behavioral and neuropathological alterations elicited by CNS-specific KO of SELENOI in mice; 2) Determine the cell-type specific contribution of SELENOI to phospholipid synthesis, ferroptotic vulnerability, and myelination in vitro using primary neurons and oligodendrocytes. The anticipated outcomes of these experiments are: 1) identification of the behaviors, brain regions, and cell types negatively impacted by SELENOI deficiency, 2) discernment of the influence of SELENOI upon PE/plasmenyl PE metabolism in brain, and 3) determination of whether SELENOI alters sensitivity to ferroptosis. This work will provide mechanistic insight not attainable with human samples and will lay the framework for future studies investigating the temporal and cell-type specific role of SELENOI in brain.

硒蛋白I（Selenoprotein I，SELENOI）是一种缺乏特征性的酶，其依赖于足够的膳食硒， 表达，并已被证明催化肯尼迪的CDP-乙醇胺分支的最终反应 内质网膜内的通路。这些途径依赖于硒的有效 磷脂酰乙醇胺（PE）和血浆磷脂酰PE是细胞内重要磷脂， 膜。虽然存在于全身的各种细胞类型中，但PE和血浆PE特别是在细胞中。 富含中枢神经系统（CNS），其中它们占总膜磷脂的45%。 Plasmenyl PE是脑中主要的乙醇胺磷脂，在白色中检测到最高水平 物质，并在优先被活性氧靶向的sn-1位含有乙烯基醚键 物种以这种方式，血浆蛋白基PE通过防止脂质过氧化而充当重要的抗氧化剂。 膜磷脂中的多不饱和脂肪酸可以引发铁凋亡（过氧化二酰基PE是一种 尤其是铁性下垂的有效执行者）。在人类中，硒的罕见突变导致遗传性 痉挛性截瘫（HSP），一种影响上运动神经元的神经退行性疾病，其特征在于 下肢功能受损。目前对管理机制的理解 脑中的PE/血浆PE代谢是有限的，这在很大程度上是由于缺乏代表性的小鼠模型， 允许进行机械研究。我们的多个主要研究者（MPI）领导的研究团队已经 开发了一种独特的小鼠模型，用于机制研究，将利用我们在硒蛋白方面的专业知识 生物化学和神经生物学，以产生关于CNS中硒功能的基础新知识。 特别是，我们已经开发了一种独特的小鼠模型，其中SELENOI缺失仅限于CNS， 从而避免了小鼠中由组成型SELENOIKO引起的胚胎致死。我们的初步 研究揭示了惊人的行为缺陷，与人类报告的罕见的丧失- 功能SELENOI突变。该项目将解决以下具体目标：1）识别和表征 CNS特异性敲除SELENOI在小鼠中引起的行为和神经病理学改变; 2） 确定硒代葡萄糖对磷脂合成、铁毒性易损性的细胞类型特异性贡献， 以及使用原代神经元和少突胶质细胞的体外髓鞘形成。这些活动的预期成果 实验是：1）识别行为，大脑区域和细胞类型的负面影响， 硒缺乏，2）识别硒对脑中PE/血浆PE代谢的影响， 和3）测定硒是否改变对铁凋亡的敏感性。这项工作将提供机械性 这是人类样本无法达到的洞察力，将为未来的研究奠定框架， 硒在脑中时间和细胞类型特异性作用。