Dissect the mechanisms of selective regional vulnerability in Lewy Body Dementias via comparative snRNA-seq analysis

项目摘要 路易体病是一种高度异质性的神经退行性疾病，包括帕金森氏症 帕金森氏病(PD)、帕金森氏病痴呆(PDD)和路易体痴呆(DLB)。LBD是 以蛋白α-突触核蛋白在神经元胞体(路易小体)和 神经突起，目前被认为是这些疾病的共同原因。刘易体沉积开始 帕金森病患者的尾侧脑干有阳性表达，而DLB患者的大脑皮质有阳性表达。起始α-突触核蛋白的区域差异 沉积与相应区域的神经元丢失相关-黑质中的多巴胺神经元 (SN)和新皮质中身份不明的神经元，其独特的临床表现以 帕金森病患者有运动症状，而迟发性痴呆患者有早期痴呆。为什么某些特定的神经元和大脑区域 在发病时受到影响，而邻近的细胞和区域没有？这是中的一个基本问题 这项提案将通过新的基因组学技术和 生物信息学工具。在最初的先导研究中，我们使用单核rna测序(snrna-seq)分析。 发现了一种新的疾病相关星形胶质细胞(DAA)亚群，并证明DAA对 炎症增加，淀粉样蛋白病理和神经退行性疾病的发病机制 实质性星形胶质细胞在阿尔茨海默病和帕金森病脑中的功能都有损害。此外，我们还确定了 三个小胶质细胞亚群，它们与小胶质细胞相似，但具有不同于 常规静息(M0)、M1和M2激活小胶质细胞。我们观察到共有的小胶质细胞功能缺陷 帕金森病患者所有小胶质细胞亚群和独特的上调炎症途径提示共同 以及帕金森病特有的神经退行性变机制。这些数据为我们提供了独一无二的机会 分析这些神经胶质细胞亚群与选择性局部和神经元易损性之间的关系 不同的疾病。在目标1中，我们将确定患者额叶皮质(FC)和SN中易受攻击的神经元类型 使用PD、PDD和DLB。在目标2中，我们将检验星形胶质细胞/小胶质细胞功能障碍是 LBD的选择性区域脆弱性的机制。在目标3中，我们将检验这一假设 神经元与星形胶质细胞/小胶质细胞的相互作用是选择性神经元发生机制的基础 LBD的漏洞。我们的研究将对选择性神经元的分子机制提供更深入的见解。 和LBD的地区性脆弱性。此外，我们的研究还将为神经元提供分子生物学标记物和工具 细胞类型特异性保护和靶向星形胶质细胞/小胶质细胞亚群的分离和操纵。 此外，我们的研究还将提供区分PD、PDD和DLB的分子生物标志物，这是非常有意义的 这很重要，但在今天是一个相当大的挑战。

Project Summary Lewy body diseases (LBDs) are highly heterogeneous neurodegenerative disorders including Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB). LBDs are characterized by the abnormal aggregation of the protein α-synuclein in neuronal cell bodies (Lewy Body) and neurites which are currently considered to be the common cause of the diseases. Lewy Body deposition starts in the caudal brainstem of PD but in the neocortex of DLB cases. The regional differences of initial α-synuclein deposition correlate with neuronal loss in the corresponding regions - dopamine neurons in the substantia nigra (SN) and neurons of unknown identity in the neocortex, and the unique clinical manifestations with a predominant motor symptom in PD whereas early dementia in DLB. Why some particular neurons and brain regions are affected at the disease onset, whereas the neighboring cells and regions not? This is a fundamental question in the field of neurodegenerative diseases that this proposal will address via novel genomics technologies and bioinformatics tools. In an initial pilot study, using single nucleus RNA-sequencing (snRNA-seq) analyses, we identified a novel disease-associated astrocyte (DAA) subpopulation and demonstrated that DAA contributed to increased inflammation, amyloid pathology, and neurodegenerative disease pathogenesis whereas parenchymal astrocytes had compromised functionality in both AD and PD brains. Additionally, we identified three microglia subpopulations that were similar to but with marker gene expression profiles distinct from the conventional resting (M0), M1, and M2 activated microglia. We observed deficient microglia functionality shared across all microglia subpopulations and uniquely up-regulated inflammatory pathways in PD suggesting common and PD-specific mechanisms of neurodegeneration. These data provide us with an exclusive opportunity to analyze the relationships between these glia subpopulations and selective regional and neuronal vulnerability in different diseases. In Aim 1, we will identify vulnerable neuronal types in the frontal cortex (FC) and SN of patients with PD, PDD, and DLB. In Aim 2, we will test the hypothesis that astrocyte/microglia dysfunction underlies the mechanism of the selective regional vulnerability of LBD. In Aim 3, we will test the hypothesis that dysregulated interactions between neurons and astrocytes/microglia underlie the mechanism of the selective neuronal vulnerability of LBD. Our study will provide deep insights into the molecular mechanisms of selective neuronal and regional vulnerability in LBDs. Besides, our study will provide molecular biomarkers and tools for neuron cell-type-specific protection and targeted astrocyte/microglia subpopulation isolation and manipulation. Furthermore, our study will provide molecular biomarkers for distinguishing PD, PDD, and DLB, which is very important but a considerable challenge today.