Role of the endolysosomal pathway in Lewy body dementia - from population genomics to single cells

项目摘要/摘要 最常见的阿尔茨海默病相关痴呆症(ADRD)之一是路易体痴呆。这 总括术语包括两种临床上不同的ADRD：帕金森氏病痴呆(PD-痴呆)和 路易体痴呆(DLB)。然而，人们对DLB的遗传基础越来越感兴趣， 帕金森氏病-痴呆症还没有使用大规模的遗传分析进行研究。然而，它已经被证明是 内溶酶体途径功能障碍在阿尔茨海默病和ADRDS中起着关键作用。这 然而，参与其中的原因还不完全清楚，每种疾病的确切故障点还没有确定。 已确认身份。因此，人们对每一种疾病的具体分子机制的认识都存在差距。 疾病。这项应用旨在识别调节帕金森氏病痴呆风险的遗传变异性及其 神经病理特征，确定与其他ADRDS的重叠和直接的下游影响 关于内溶酶体功能。基于初步数据的假设是，帕金森氏症痴呆症有可测量的 和独特的遗传结构，以及它与其他生物分子基础的现有知识的整合 ADRDS，将提高对溶酶体作为神经退行性变的中枢病理枢纽的理解 疾病。这一假设将通过追求三个具体目标来检验：1)确定候选的风险调节 帕金森氏病痴呆的变种；2)确定遗传风险的神经病理相关性；3)确定下游 ADRD中神经元和神经胶质细胞的高风险变异性的影响。一组临床诊断为帕金森病的患者- 痴呆症病例和一组神经病理诊断病例将在GWAS框架下进行测试 在一项分两个阶段的研究中确定风险调节的变种。神经病理病例也将接受完整的- 基因组测序以识别常见和罕见的遗传变异，从而实现了第一次基因组学研究 大量帕金森氏病痴呆病例的神经病理学金标准特征。最后，即刻 通过在大脑中进行单细胞rna-seq，将确定特定于疾病的风险描述的特定细胞效应。 这两种ADRD和AD的多基因风险最高的个体的组织。建议数 首次将研究重点放在帕金森病患者身上，作为严格的诊断，利用大规模 不偏不倚的基因分析，并将其与相关疾病结合起来。这项拟议的研究具有重要意义 因为它将提供路易体痴呆症特有的复合基因图谱。建议进行的研究 设计有可能识别不同形式的ADRD共同的靶点，以及新奇的， 个性化的、针对疾病的目标；这项建议是对国家阿尔茨海默氏症项目的直接回应 《国家适应行动方案》公法111-375、国家适应行动方案2012-2013和国家适应行动方案2016。

PROJECT SUMMARY/ABSTRACT One of the most common Alzheimer’s Disease Related Dementias (ADRD) is Lewy body dementia. This umbrella term comprises two clinically distinct ADRDs: Parkinson’s disease dementia (PD-dementia) and dementia with Lewy bodies (DLB). There has been a growing interest in the genetic bases of DLB, however, PD-dementia has not yet been studied using large-scale genetic analyses. Nevertheless, it has been shown that dysfunction of the endolysosomal pathway plays a key role in Alzheimer’s disease and ADRDs. This involvement, however, is not fully understood and the exact failure points for each disease have yet to be identified. Thus, there is a gap in knowledge regarding the specific molecular mechanisms underlying each disease. This application aims to identify genetic variability that modulates risk for PD-dementia and its neuropathological features, determining the overlap with other ADRDs and the immediate downstream effects on endolysosomal function. The hypothesis, based on preliminary data, is that PD-dementia has a measurable and unique genetic architecture and that its integration with current knowledge of the molecular bases of other ADRDs, will improve the understanding of the lysosome as a central pathological hub in neurodegenerative diseases. This hypothesis will be tested by pursuing three specific aims: 1) identify candidate risk-modulating variants for PD-dementia; 2) determine neuropathological correlates of genetic risk; and 3) identify downstream effects of high-risk variability in neurons and glial cells across ADRDs. One cohort of clinically diagnosed PD- dementia cases and one cohort of neuropathological diagnosed cases will be tested under a GWAS framework to identify risk modulating variants in a two-stage study. The neuropathological cases will also undergo whole- genome sequencing to identify common and rare genetic variability, allowing for the first genomics study with gold-standard characterization of neuropathology in a large cohort of PD-dementia cases. Last, the immediate cell-specific effects of disease-specific risk profile will be determined by performing single-cell RNA-seq in brain tissue from individuals with the highest polygenic risk for each of these two ADRDs and for AD. The proposed research focuses for the first time on PD-dementia cases, as a strict diagnosis, taking advantage of large-scale unbiased genetic analyses and integrating that with related disorders. The proposed research is significant because it will provide a composite genetic profile specific for this Lewy body dementia. The proposed study design has the potential to identify targets that are common to different forms of ADRDs, as well as novel, personalized, disease-specific targets; this proposal is a direct response to the National Alzheimer's Project Act (NAPA) Public Law 111-375, NAPA 2012 2013, and NAPA 2016.