HLA genetics and Parkinson's disease

HLA 遗传学和帕金森病

• 批准号: 10609700
• 负责人: Alessandro Didonna
• 金额: $ 37.01万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609700
• 关键词: HLA; genetics; Parkinson; disease

Summary Genetic variation is an important determinant of Parkinson's disease (PD) risk and progression. Advances in genomic technologies coupled with access to large DNA collections have set in place the foundation to fully describe the genetic component of PD pathogenesis. However, genetic research will fall short of its potential to improve patients' outcomes until we identify the mechanisms underlying the statistical associations. The focus of this proposal is to explore the biology of HLA-mediated susceptibility in PD using genetic, immunological, and computational approaches. We hypothesize that a specific combination of amino acids at positions 70-74 on the α-helix of the HLA-DRβ1 molecule, defining the sides of the HLA peptide-binding groove, drives disease risk or protection through specific adaptive immune responses. We also hypothesize that HLA-cell surface calreticulin interactions in the CNS modulate microglia scavenging activity and neuronal survival. Our preliminary data suggest that these alternative hypotheses are not necessarily in conflict. To address our goals, we will merge genetic and experimental datasets representing PD susceptibility and pathological hallmarks, bringing together expertise in genomics, proteomics, molecular modelling and cellular neurobiology. Specific Aim 1 describes at high resolution the HLA genetic variation associated with PD in non-European datasets, and characterizes the molecular mechanisms underlying the association at both, functional and structural levels. Specific Aim 2 explores the hypothesis that HLA contribution to PD is independent from classic antigen-presentation processes, and rather functions via surface calreticulin- mediated signaling. Lastly, in Specific Aim 3, we will generate the first humanized PD mouse model overexpressing wildtype α-synuclein and carrying a protective HLA allele in order to dissect the influence of this locus on PD phenotypes in a complex in vivo biological environment. Altogether, the proposed aims hold the power to substantially advance the current understanding of PD pathogenesis, with lessons for other neurodegenerative diseases, including the related synucleinopathy Lewy body dementia (LBD).

概括 遗传变异是帕金森病 (PD) 风险和进展的重要决定因素。 基因组技术与大量 DNA 收藏相结合，为充分利用基因组技术奠定了基础。 描述 PD 发病机制的遗传成分 然而，遗传研究将无法发挥其潜力。 改善患者的治疗效果，直到我们确定统计关联背后的机制。 该提案的重点是利用遗传、 我们捕获了氨基酸的特定组合。 HLA-DRβ1 分子 α 螺旋上的位置 70-74，定义了 HLA 肽结合的侧面 凹槽，通过特定的适应性免疫反应驱动疾病风险或保护。 CNS 中 HLA 细胞表面钙网蛋白相互作用调节小胶质细胞清除活性和神经元 我们的初步数据表明，这些替代假设不一定是冲突的。 为了实现我们的目标，我们将合并代表 PD 易感性的遗传和实验数据集 病理标志，汇集了基因组学、蛋白质组学、分子建模和细胞方面的专业知识 神经生物学。具体目标 1 以高分辨率描述与 PD 相关的 HLA 遗传变异。 非欧洲数据集，并描述了两者之间关联的分子机制， 具体目标 2 探讨了 HLA 对 PD 的贡献是的假设。 独立于经典的抗原呈递过程，而是通过表面钙网蛋白发挥作用 最后，在特定目标 3 中，我们将生成第一个人源化 PD 小鼠模型。 过度表达野生型 α-突触核蛋白并携带保护性 HLA 等位基因，以剖析以下因素的影响 总而言之，所提出的目标是在复杂的体内生物环境中的 PD 表型上实现的。 能够大幅推进当前对帕金森病发病机制的理解，并为其他人提供经验教训 神经退行性疾病，包括相关的突触核蛋白病路易体痴呆（LBD）。