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).

总结 遗传变异是帕金森病（PD）风险和进展的重要决定因素。进展 基因组技术加上获得大量DNA集合已经奠定了基础， 描述PD发病机制的遗传成分。然而，基因研究将达不到其潜力 以改善患者的治疗结果，直到我们确定统计学关联背后的机制。的 该建议的焦点是利用遗传学， 免疫学和计算方法。我们假设，一种特定的氨基酸组合， HLA-DR β 1分子α-螺旋上的70 - 74位，定义HLA肽结合的两侧 沟，驱动疾病的风险或通过特定的适应性免疫反应的保护。我们还假设 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 生存我们的初步数据表明，这些替代假设不一定相互冲突。 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 神经生物学特定目标1以高分辨率描述了与PD相关的HLA遗传变异， 非欧洲的数据集，并表征了在这两个协会的分子机制， 功能和结构层面。具体目标2探讨了HLA对PD的贡献是 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， 介导的信号传导。最后，在具体目标3中，我们将产生第一个人源化PD小鼠模型 过表达野生型α-突触核蛋白并携带保护性HLA等位基因，以分析 在复杂的体内生物学环境中，该基因座对PD表型的影响。总的来说， 大幅度推进目前对PD发病机制的理解的力量，为其他 神经变性疾病，包括相关的突触核蛋白病路易体痴呆（LBD）。