Roles of autophagy in microglial senescence and Parkinson's disease

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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.