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) 是一种特性较差的酶，其功能依赖于充足的膳食硒 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 内质网膜内的通路。这些途径依赖于 SELENOI 的有效 磷脂酰乙醇胺 (PE) 和纤浆烯基 PE 的合成，它们是细胞中重要的磷脂 膜。尽管 PE 和 plasmenyl PE 存在于全身各种细胞类型中，但它们尤其重要。 富含中枢神经系统 (CNS)，占总膜磷脂的 45%。 Plasmenyl PE 是大脑中主要的乙醇胺磷脂，在白色中检测到的含量最高 物质，并在 sn-1 位上含有乙烯基醚键，该键优先被活性氧靶向 物种。通过这种方式，plasmenyl PE 通过防止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引发铁死亡（过氧化二酰基 PE 是一种 特别有效的铁死亡刽子手）。在人类中，SELENOI 的罕见突变会导致遗传性 痉挛性截瘫 (HSP)，一种影响上运动神经元的神经退行性疾病，其特征为 下肢功能受损。目前对治理机制的理解 PE/plasmenyl PE 在大脑中的代谢是有限的，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。我们的多位首席研究员 (MPI) 领导的研究团队 开发了一种用于机制研究的独特小鼠模型，该模型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，产生有关中枢神经系统 SELENOI 功能的基本新知识。 特别是，我们开发了一种独特的小鼠模型，其中 SELENOI 删除仅限于中枢神经系统， 从而避免了小鼠中由组成型SELENOI KO引起的胚胎致死。我们的初步 研究揭示了惊人的行为缺陷，与罕见的丧失行为的人类相似。 功能SELENOI突变。该项目将实现以下具体目标： 1) 识别和表征 SELENOI 的 CNS 特异性 KO 引起的小鼠行为和神经病理学改变； 2） 确定 SELENOI 对磷脂合成、铁死亡脆弱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进行体外髓鞘形成。这些的预期结果 实验是：1）识别受负面影响的行为、大脑区域和细胞类型 SELENOI 缺乏症，2) 辨别 SELENOI 对大脑中 PE/plasmenyl PE 代谢的影响， 3) 确定 SELENOI 是否改变对铁死亡的敏感性。这项工作将提供机械 人类样本无法获得的洞察力将为未来研究奠定框架 SELENOI 在大脑中的时间和细胞类型特定作用。