Early Onset Parkinson’s disease subtypes and pathogenic mechanisms

摘要 帕金森氏病是不同亚型的总称，表现为不同的临床特征和不同的 潜在的致病机制。遗传、炎症和α-突触核蛋白的积聚是主要原因 疾病的致病动因，在患者亚群中发挥着不同的作用。根据以下因素对患者进行分层 在精准医学的场景中，主要的致病机制正在成为关键。广泛性 这些致病机制在早发性帕金森病(EOPD)中的作用特征如下 缺乏。EOPD是一种罕见的疾病，患者在50岁之前表现出帕金森病，因此影响 这些受试者生活的很大一部分。我们的中心假设是，EOPD意味着不同的亚类型 预后与遗传、炎症和α-突触核蛋白的不同贡献有关的患者 在他们的发病机制中积聚。这项提案的总体目标将是描述贡献的特征 遗传学、炎症和α-突触核蛋白在EOPD大队列中的积聚，并评估这些因素是如何 机制可以指导EOPD亚型的识别。为了实现这一目标，这一行动的主要目标 建议将集中于1)描述大量EOPD患者的临床和基因特征；2)评估 中枢和外周生物样本中α-突触核蛋白的存在；3)分析中枢和外周生物样本 与迟发性帕金森病(LOPD)和未受影响的受试者(CTRL)相比，EODP炎性激活。对于 首先，我们将对EOPD患者群体进行深入的表型表征，并确定 通过无偏见的等级聚类分析进行表型聚类。受试者也将被基因分析 通过全基因组测序(WGS)来识别已知和新的遗传变异，并用于 稀有基因变异的负担分析。在第二个目标中，我们将评估α-突触核蛋白扩增分析，一 联核病最有希望的创新生物标记物，皮肤活检和脑脊液 EOPD。在第三个目标中，我们将描述单细胞数据和广泛的蛋白质组的表达谱 EOPD、LOPD和CTRL的外周血液和脑脊液炎症标志物小组，至 确定EOPD中的炎性激活并表征细胞特异性(先天免疫与获得性免疫)。 最后，我们将关联来自三个目标的数据，以评估遗传学、临床、炎症性和 EOPD亚型中的生物标志物数据。虽然目前对这一主题的研究大多集中在单个方面 对于这种疾病，这项研究建议是创新的，因为它将不同的疾病机制联系起来，以检测 EOPD亚型。这一项目的主要意义将是提供新的见解，以发病机制。 EOPD将为EOPD机制驱动的治疗方法的设计提供信息，提供 为患者咨询提供有用信息，并为临床试验对患者进行分层。

ABSTRACT Parkinson’s disease is an umbrella of different subtypes that manifest with distinct clinical features and different underlying pathogenic mechanisms. Genetics, inflammation, and accumulation of alpha-synuclein are the main pathogenic drivers of the disease, playing a different role in sub-groups of patients. Stratifying patients based on the main pathogenic mechanisms is becoming key in the scenario of precision medicine. Extensive characterization of the role of these pathogenic mechanisms in early onset Parkinson’s disease (EOPD) is lacking. EOPD is a rare condition where PD manifests in patients before the age of 50 years and thus affecting large part of the lives of these subjects. Our central hypothesis is that EOPD implies different sub-types of patients with prognostic outcomes related to diverse contribution of genetics, inflammation and alpha-synuclein accumulation in their pathogenesis. The overall objective of this proposal will be to characterize the contribution of genetics, inflammation, and alpha-synuclein accumulation in large cohort of EOPD and assess how these mechanisms can guide the identification of EOPD sub-types. To achieve this objective the main aims of this proposal will focus on 1) characterizing the clinical and genetic profile of a large cohort of EOPD; 2) assessing the presence of alpha-synuclein in central and peripheral biosamples; 3) profiling the central and peripheral inflammatory activation of EODP compared to late onset PD (LOPD) and non-affected subjects (CTRL). For the first aim we will perform a deep phenotypical characterization of a population of EOPD patients and identify phenotypical clusters through an unbiased hierarchical cluster analysis. Subjects will also be profiled genetically through Whole Genome Sequencing (WGS) for the identification of known and new genetic variants, and for burden analysis of rare gene variants. In the second aim we will assess alpha-synuclein amplification assay, one of the most promising innovative biomarkers for synucleinopathy, on skin biopsies and CSF of subjects with EOPD. In the third aim we will characterize the expression profiles of single cells data and an extensive proteomic panel for inflammatory markers from peripheral blood and cerebrospinal fluid of EOPD, LOPD and CTRL, to determine inflammatory activation in EOPD and characterize cell-specific (innate vs adaptive immunity). Finally, we will correlate data from the three aims to assess the profiles of genetics, clinical, inflammatory, and biomarkers data in EOPD sub-types. While most of the current research on this topic focuses on single aspects of the disease, this research proposal is innovative because it correlates different disease mechanisms to detect subtypes of EOPD. The main significance of this project will be to provide new insights in the pathogenesis of EOPD which will be informative to the design of mechanism-driven therapeutic approaches for EOPD, provide useful information for patient counseling, and stratify patients for clinical trials.