Defining the role of C. elegans Parkin/PDR-1 in glial engulfment of neuron fragments

定义线虫 Parkin/PDR-1 在胶质细胞吞噬神经元片段中的作用

• 批准号: 10158183
• 负责人: STEPHAN RAIDERS
• 金额: $ 4.04万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158183
• 关键词: Adult; Afferent Neurons; Alzheimer' s disease model; Apoptotic; Biochemical; Biological Assay; Biological Models; Biotin; Caenorhabditis elegans; Cells; Chimeric Proteins; Data; Development; Developmental Process; Disease; Drosophila genus; Eating; Eye; Genes; Guanosine Triphosphate Phosphohydrolases; Impairment; Insecta; Invertebrates; Kinetics; Label; Learning; Link; Macular degeneration; Mammals; Measures; Mediating; Methods; Mitochondria; Modeling; Nerve Degeneration; Nervous system structure; Neuroglia; Neuronal Dysfunction; Neurons; Orthologous Gene; Parkin; Parkinson Disease; Pathway interactions; Peptides; Peripheral Nervous System; Phagocytes; Phagocytosis; Pharmacology; Process; Proteins; Regulation; Role; Sensory; Shapes; Signal Transduction; Structure; Structure of retinal pigment epithelium; Synapses; System; Training; Ubiquitin; Ubiquitination; base; experimental study; in vivo; insight; loss of function; loss of function mutation; member; mitochondrial membrane; mouse model; nervous system disorder; null mutation; protein profiling; ubiquitin-protein ligase

PROJECT SUMMARY Glia engulf fragments of live neurons in order to regulate specialized neuron endings. Amounting evidence indicates the engulfment of neuron fragments by glia is a broad regulatory and developmental function of glia in both the central and peripheral nervous systems. How this process is regulated under normal conditions is unclear in any system, but it was recently shown that mis-regulation of this process contributes to early synapse loss in mouse models of Alzheimer’s disease. Furthermore, mis-regulation of phagocytosis by Retinal Pigment Epithelium cell in the eye may cause some forms of macular degeneration. Synapse loss and sensory disfunction are early hallmarks of Parkinson’s disease, however the involvement of glia is unknown. Loss of function of the E3 ubiquitin ligase Parkin contributes to the onset and progression of Parkinson’s disease. The role of Parkin mediating mitophagy in neurons is well characterized in mammals and invertebrate models, but despite being expressed in several glial subtypes, the functions of Parkin in glia are unknown. We have recently shown in C. elegans that fragments of a specialized sensory neuron are engulfed by an associated glial cell. Preliminarily, I have found that loss of function of the Parkin ortholog pdr-1 elicits a substantial increase in the number neuron fragments engulfed by glia, demonstrating that PDR-1 inhibits engulfment by glia. C. elegans has historically been a powerful model used to unearth the mechanisms of phagocytosis by which cells recognize, engulf, and degrade cellular debris. I propose to use this system to probe the mechanism by which Parkin/PDR-1 regulates glial phagocytosis of neuron fragments. I will determine the cell-specific requirements of PDR-1, probe substrates of its E3 ligase activity that may have roles in glial engulfment, and finally ask if its role in mitophagy has a function in glial engulfment.

项目概要 神经胶质细胞吞噬活神经元的碎片，以调节专门的神经元末梢。收集证据 表明神经胶质细胞吞噬神经元片段是神经胶质细胞广泛的调节和发育功能 中枢神经系统和周围神经系统。在正常情况下这个过程是如何调节的 在任何系统中尚不清楚，但最近表明，该过程的错误调节会导致早期突触 阿尔茨海默病小鼠模型的损失。此外，视网膜色素对吞噬作用的错误调节 眼睛中的上皮细胞可能会导致某些形式的黄斑变性。突触损失和感觉 功能障碍是帕金森病的早期标志，但神经胶质细胞的参与尚不清楚。损失 E3 泛素连接酶 Parkin 的功能有助于帕金森病的发病和进展。这 Parkin 在神经元中介导线粒体自噬的作用在哺乳动物和无脊椎动物模型中得到了很好的表征，但是 尽管 Parkin 在几种神经胶质细胞亚型中表达，但 Parkin 在神经胶质细胞中的功能尚不清楚。我们最近有 线虫中显示，特殊感觉神经元的片段被相关的神经胶质细胞吞噬。 初步地，我发现 Parkin 直系同源物 pdr-1 的功能丧失会导致 被神经胶质细胞吞噬的神经元碎片数量，表明 PDR-1 抑制神经胶质细胞的吞噬。线虫 历史上一直是一个强大的模型，用于揭示细胞的吞噬作用机制 识别、吞噬和降解细胞碎片。我建议使用这个系统来探究其机制 Parkin/PDR-1 调节神经胶质细胞对神经元片段的吞噬作用。我将确定细胞的具体要求 PDR-1，探测其E3连接酶活性的底物，该活性可能在神经胶质吞噬中起作用，最后询问其作用是否 在线粒体自噬中具有神经胶质吞噬的功能。