Roles of autophagy in microglial senescence and Parkinson's disease

自噬在小胶质细胞衰老和帕金森病中的作用

• 批准号: 10664560
• 负责人: Insup Choi
• 金额: $ 12.59万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664560
• 关键词: Affect; Age; Aging; Alzheimer' s disease model; Animal Disease Models; Animal Model; Area; Autophagocytosis; Autophagosome; Autopsy; Bacteria; Biological Assay; Blood; Brain; Brain Diseases; CRISPR/Cas technology; Cathepsins; Cell Aging; Cells; Cellular Morphology; Chronic; Cyclin-Dependent Kinase Inhibitor; DNA Damage; Data; Degradation Pathway; Disease; Disease Progression; Essential Genes; Excision; Exhibits; Freezing; Gene Expression Profile; Genes; Genetic; Genomics; Health; Homeostasis; Human; In Situ Hybridization; Inflammation; Invaded; Ligation; Lipofuscin; Longevity; Lysosomes; Macrophage; Mass Spectrum Analysis; Microglia; Molecular Profiling; Movement Disorders; Mus; Neurodegenerative Disorders; Neuroglia; Neurons; Organ; Organelles; Parkinson Disease; Pathogenicity; Pathway interactions; Patients; Phenotype; Process; Proliferating; Proteins; RNA; Reporting; Research; Risk Factors; Role; SNAP receptor; Substantia nigra structure; Surveys; Technology; Testing; age effect; age related; alpha synuclein; anti aging; brain tissue; cell injury; cognitive impairment in Parkinson' s; comparison control; disease phenotype; dopaminergic neuron; induced pluripotent stem cell; inflammatory marker; inhibition of autophagy; insight; knock-down; misfolded protein; motor impairment; multiple omics; neuronal survival; neuroprotection; pars compacta; prevent; protein aggregation; proteomic signature; response; senescence; single nucleus RNA-sequencing; syntaxin; therapeutic target; transcriptome sequencing; transcriptomics

Project Summary Parkinson’s disease (PD) is the most common age-dependent movement disorder; however, it remains mysterious how aging predisposes the brain to PD. As the body ages, senescent cells become accumulated in multiple organs, including the brain. Recent evidence showed that removal of senescent glial cells, including microglia, alleviates disease phenotypes in animal models of Alzheimer’s disease (AD) and PD. Microglia are brain-specific macrophages that continuously survey the brain to maintain brain homeostasis. Senescent microglia may lose their neuroprotective functions and secret senescence-associated secretory phenotype (SASP), leading to chronic inflammation. Therefore, there is a critical need to examine the impact of senescent microglia on human PD. Our preliminary data with single-nucleus RNA sequencing (snRNA-seq) technology revealed that a subset of microglia expresses more senescence-related genes in human PD brain. The long- term objectives of this research are to elucidate whether and how microglia become senescent in PD and to characterize the molecular signature of senescent microglia for finding out therapeutic targets. In Aim1, we will determine whether senescent microglia become accumulated in PD and establish the relationship between autophagic flux and microglial senescence using human PD postmortem brain. Autophagy is a cellular degradation pathway responsible for removing damaged cellular organelles, protein aggregates, and invading foreign substances. Autophagy plays a role in extending healthy lifespan and preventing cellular senescence in animal models. Our preliminary data highlights that autophagy prevents microglial senescence in mouse. In Aim2, we will characterize the transcriptomic and proteomic signatures of senescent microglia in human PD postmortem brain by employing snRNA-seq and spatial omics technologies. In Aim 3, we will utilize human microglia from induced pluripotent stem cells (iPSC) to study the roles of autophagy in microglial senescence. We will apply RNA-seq and LC-MS/MS to elucidate the transcriptomic profile and SASP of senescent microglia, respectively. Lastly, we will determine the effect of SASP from senescent microglia on the survival of human dopaminergic neurons. Successful completion of this project will 1) provide evidence for microglial senescence in human PD brain, 2) characterize the molecular signature of senescent microglia, and 3) provide insight into the mechanism of how autophagy regulates microglial senescence and how senescent microglia affect dopaminergic neurons.

项目摘要 帕金森病（PD）是最常见的年龄依赖性运动障碍;然而，它仍然是 衰老如何使大脑易患帕金森病这一神秘问题随着身体的衰老，衰老的细胞会聚集在 多个器官包括大脑最近的证据表明，去除衰老的神经胶质细胞，包括 在阿尔茨海默病（AD）和PD的动物模型中描述疾病表型。小胶质细胞是 脑特异性巨噬细胞，持续监测大脑以维持大脑稳态。衰老 小胶质细胞可能失去其神经保护功能，并分泌衰老相关的分泌表型 （SASP），导致慢性炎症。因此，迫切需要研究衰老的影响 小胶质细胞对PD的影响我们的初步数据与单核RNA测序（snRNA-seq）技术 揭示了一个小胶质细胞亚群在人类PD脑中表达更多的衰老相关基因。很长的- 本研究的长期目标是阐明PD中小胶质细胞是否以及如何衰老， 表征衰老小胶质细胞的分子特征以寻找治疗靶点。在AIM 1中，我们将 确定衰老的小胶质细胞是否在PD中积累，并建立 使用人PD死后脑的自噬通量和小胶质细胞衰老。自噬是一种 降解途径，负责清除受损的细胞器，蛋白质聚集体，并侵入 异物。自噬在延长健康寿命和防止细胞衰老方面发挥作用， 动物模型我们的初步数据强调了自噬可以防止小鼠小胶质细胞衰老。在 目的2，我们将描述人类PD中衰老小胶质细胞的转录组学和蛋白质组学特征 通过snRNA-seq和空间组学技术，在目标3中，我们将利用人类 从诱导多能干细胞（iPSC）的小胶质细胞，以研究自噬在小胶质细胞衰老中的作用。 我们将应用RNA-seq和LC-MS/MS来阐明衰老小胶质细胞的转录组学特征和SASP， 分别最后，我们将研究衰老小胶质细胞SASP对人存活的影响。 多巴胺能神经元本项目的成功完成将1）提供小胶质细胞衰老的证据 在人类PD脑中，2）表征衰老小胶质细胞的分子特征，3）提供对 自噬调控小胶质细胞衰老的机制以及衰老的小胶质细胞如何影响 多巴胺能神经元