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

内溶酶体途径在路易体痴呆中的作用——从群体基因组学到单细胞

• 批准号: 10368526
• 负责人: Jose Bras
• 金额: $ 94.95万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368526
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Architecture; Brain; Cations; Cells; Clinical; Data; Dementia; Dementia with Lewy Bodies; Development; Diagnosis; Disease; Failure; Foundations; Functional disorder; Future; Genetic; Genetic Risk; Genetic Transcription; Genetic study; Genomics; Genotype; Goals; Gold; Grant; Healthcare; Human Genetics; Individual; International; Intervention; Knowledge; Laws; Lewy Body Dementia; Lewy Body Disease; Lysosomes; Measurable; Mission; Modeling; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Play; Population; Research; Research Design; Research Priority; Risk; Role; Sampling; Small Nuclear RNA; Societies; Testing; Therapeutic Intervention; Time; United States National Institutes of Health; Variant; Work; base; brain tissue; cellular pathology; clinical Diagnosis; cognitive impairment in Parkinson' s; cohort; dementia risk; genetic analysis; genetic architecture; genetic variant; genome sequencing; genome wide association study; high risk; improved; in vivo; insight; interest; neuropathology; new therapeutic target; novel; response; risk variant; single-cell RNA sequencing; synuclein; synucleinopathy; trafficking; virtual; ward; whole genome

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.

项目总结/摘要 最常见的阿尔茨海默病相关性痴呆（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， PD痴呆症尚未使用大规模遗传分析进行研究。尽管如此， 内溶酶体途径功能障碍在阿尔茨海默病和ADRD中发挥着关键作用。这 然而，参与还没有完全了解，每种疾病的确切失败点还没有被确定。 鉴定因此，关于每种疾病背后的具体分子机制， 疾病本申请旨在确定调节PD痴呆风险的遗传变异性及其 神经病理学特征，确定与其他ADRD的重叠和直接下游效应 对内溶酶体功能的影响基于初步数据的假设是，PD痴呆具有可测量的 和独特的遗传结构，并将其与目前对其他基因的分子基础的知识相结合， ADRD将提高对溶酶体作为神经退行性疾病中的中心病理枢纽的理解。 疾病这一假设将通过追求三个具体目标进行检验：1）确定候选风险调节 PD痴呆的变异; 2）确定遗传风险的神经病理学相关性; 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。一组临床诊断的PD- 将在GWAS框架下对一组痴呆病例和一组神经病理学诊断病例进行测试 在两阶段研究中识别风险调节变异。神经病理学病例也将接受整个- 基因组测序，以确定常见和罕见的遗传变异，允许第一个基因组学研究， PD痴呆病例大队列中神经病理学的金标准表征。最后，立即 将通过在脑中进行单细胞RNA-seq来确定疾病特异性风险特征的细胞特异性效应 来自这两种ADRD和AD的多基因风险最高的个体的组织。拟议 研究首次集中在PD痴呆病例上，作为严格的诊断，利用大规模的 无偏见的基因分析，并将其与相关疾病相结合。所提出的研究是有意义的 因为它能提供路易体痴呆症的复合基因图谱拟定研究 设计有可能识别不同形式ADRD共有的靶点，以及新的， 个性化，疾病特异性目标;该提案是对国家阿尔茨海默病项目的直接回应 《国家适应行动计划》（NAPA）公法111-375，NAPA 2012 2013和NAPA 2016。