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

基本信息

批准号：
10632307
负责人：
STEPHAN RAIDERS
金额：
$ 2.92万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10632307
关键词：
Adult Afferent Neurons Alzheimer&apos 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 Insecta Invertebrates Kinetics Label Learning Link Macular degeneration Mammals Measures Mediating Methods Mitochondria Modeling 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 macula member mitochondrial membrane mouse model nervous system disorder null mutation ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Glia engulf fragments of live neurons in order to regulate specialized neuron endings1,2. 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 disease3. 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 unknown4,5. 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,6 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 debris7. 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碎片以调节专门的神经元末梢1,2。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如何调节这一过程。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3 此外，视网膜色素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和感觉丧失。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4,5。 E3 泛素连接酶 Parkin 的功能有助于帕金森病的发病和进展。 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，6 但尽管 Parkin 在多种神经胶质细胞亚型中表达，但我们最近仍不清楚 Parkin 在神经胶质细胞中的功能。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 抑制线虫神经胶质细胞的吞噬。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我建议使用该系统来探索识别、吞噬和降解细胞碎片的机制。 Parkin/PDR-1 调节神经胶质细胞对神经元片段的吞噬作用，我将确定其细胞特异性要求。 PDR-1，探测其E3连接酶活性的底物，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。