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（Selenoi）是一种特征较差的酶，取决于足够的饮食硒。 表达并已被证明可以催化肯尼迪的CDP-乙醇胺分支的最终反应 内质网膜内的途径。这些途径取决于Selenoi的高效 磷脂酰乙醇胺（PE）和纤溶酶PE的合成，它们是细胞中重要的磷脂 膜。尽管在整个体内的各种细胞类型中都存在，但PE和纤溶酶PE尤其是 富含中枢神经系统（CNS），占膜总磷脂的45％。 纤溶酶PE是脑中主要的乙醇胺磷脂，白色检测到最高水平 物质，并在SN-1位置包含乙烯基醚键，该键优先用活性氧靶向 物种。以这种方式，纤溶酶PE通过防止过氧化的过氧化作为重要的抗氧化剂 膜磷脂中的多不饱和脂肪酸可以触发铁毒性（过氧化的二酰基PE为A 特别有效的铁铁作用执行者）。在人类中，硒质中的罕见突变导致遗传 痉挛性截瘫（HSP），一种影响上部运动神经元的神经退行性疾病，其特征是 下肢功能受损。当前对控制机制的理解 大脑中的PE/纤溶酶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员（MPI）领导的研究团队拥有 开发了一种独特的鼠标模型，用于机械研究，该模型将利用我们的硒蛋白专业知识 生物化学和神经生物学，以产生有关CNS中硒功能的基本知识。 特别是，我们开发了一个独特的鼠标模型，其中selenoi删除仅限于中枢神经系统， 从而规避小鼠构成型Selenoi KO引起的胚胎致死性。我们的初步 研究揭示了惊人的行为缺陷，这些缺陷与罕见丧失的人类报告的行为缺陷相似 功能Selenoi突变。该项目将解决以下特定目的：1）识别和表征 CNS特异性KO在小鼠中引起的行为和神经病理学改变。 2） 确定硒对磷脂合成的细胞类型特异性贡献，铁毒性脆弱性， 使用原发性神经元和少突胶质细胞在体外进行髓鞘化。这些预期的结果 实验是：1）鉴定行为，大脑区域和细胞类型受到负面影响 Selenoi缺乏症，2）识别硒对大脑中PE/质烯基PE代谢的影响， 3）确定硒是否会改变对铁凋亡的敏感性。这项工作将提供机械 人类样本无法获得洞察力，并将为未来研究的研究奠定框架 Selenoi在大脑中的时间和细胞类型的特异性作用。