HLA genetics and Parkinson's disease

摘要 遗传变异是帕金森病(PD)风险和进展的重要决定因素。最新进展 基因组技术加上对大型DNA收集的访问，已经奠定了充分 描述帕金森病发病的遗传成分。然而，基因研究将达不到其潜力。 以改善患者的预后，直到我们确定统计关联背后的机制。这个 这项建议的重点是探索人类白细胞抗原(HLA)介导的帕金森病易感性的生物学机制。 免疫学和计算方法。我们假设一种特定的氨基酸组合在 HLADRHLA1分子α-螺旋上的第70-74位，定义了β多肽结合的侧边 通过特定的适应性免疫反应，推动疾病风险或保护。我们还假设 中枢神经系统中人类白细胞抗原-细胞表面钙网织蛋白相互作用对小胶质细胞清除活性和神经元的影响 生死存亡。我们的初步数据表明，这些替代假设并不一定相互冲突。 为了达到我们的目标，我们将合并代表帕金森病易感性和帕金森病易感性的遗传和实验数据集 病理特征，汇集了基因组学、蛋白质组学、分子建模和细胞学方面的专业知识 神经生物学。特定目标1以高分辨率描述了与帕金森病相关的人类白细胞抗原基因变异 非欧洲数据集，并表征了两者关联背后的分子机制， 功能层面和结构层面。特定目标2探索了人类白细胞抗原对帕金森病的贡献是 独立于经典的抗原呈递过程，而是通过表面钙网织蛋白发挥作用- 中介信号。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 过表达野生型α-突触核蛋白并携带保护性等位基因 该基因座在复杂的体内生物环境中对帕金森病的表型有影响。总而言之，拟议的目标成立 显著促进当前对帕金森病发病机制的理解的力量，以及对其他人的教训 神经退行性疾病，包括相关的突触核素病，路易体痴呆(LBD)。

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).