Identifying Parkinson’s disease penetrance-modifying factors in the population-based Cooperative Health Research in South Tyrol (CHRIS) cohort

在南蒂罗尔州基于人群的合作健康研究 (CHRIS) 队列中确定帕金森病外显率改变因素

• 批准号: 443145328
• 负责人: Professorin Dr. Christine Klein
• 金额: --
• 依托单位: Eurac Research
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/443145328?language=en
• 关键词: Identifying; Parkinson; disease; penetrance; modifying

The largest described pedigree of Parkin mutation carriers (n=77) originates from South Tyrol and includes numerous heterozygous carriers of Parkin mutation carriers who develop overt symptoms of Parkinson’s disease (PD), while others may have prodromal, or no obvious symptoms. We aim to dissect out the factors that modify the penetrance of these variants, using additional mutation carriers in the Cooperative Health Research in South Tyrol (CHRIS) study (n=13,490 from the same geographical region). In the first funding period, testing whether factors that influence mitochondrial function can alter penetrance of nuclear mutations causing mitochondrial dysfunction, we observed an increased burden of mtDNA mutations in affected vs. unaffected heterozygous Parkin and PINK1 (Phosphatase and tensin homolog-induced putative kinase 1) mutation carriers and compared to non-carriers, which might explain the phenotypic (clinical, sub-clinical) discordance in these individuals with similar nuclear genetic background. However, the specificity of mtDNA variation as a penetrance marker and the molecular pathways of increased mtDNA mutation load ultimately leading to neurodegeneration, require further investigation with larger datasets. We hypothesize that there will be a penetrance-modifying interaction between mutations in PD genes and mitochondrial function, influenced by both mtDNA mutation burden and/or copy number, through mechanisms that involve mtDNA maintenance. In Objective 1, we will identify additional Parkin mutation carriers (expected total n=650) in the CHRIS study and characterize them phenotypically for signs and symptoms of prodromal or overt PD. From a successful recall-by-genotype pilot study, we have established the ethics framework to recall carriers for deeper phenotyping and identified phenotypes that appear able to distinguish carriers and non-carriers in the pilot study. Using deep mitochondrial sequencing, in Objective 2, we will determine the mtDNA mutational load and damaging mtDNA variants in blood from carriers of pathogenic Parkin variants identified in Objective 1. We will test whether these variables influence disease penetrance/expressivity, and specifically look whether it is possible to detect a threshold of mutation burden that predicts sub-clinical or clinical phenotype appearance. In Objective 3, we will test the causal link between pathogenic variants in Parkin, mtDNA mutations and expressivity of molecular phenotypes of mitochondrial function in neuronal cell models, and test mechanisms that might rescue mitochondrial function in the presence of such Parkin and mtDNA variants. We will characterize biosamples drawn from participants at different time points to see changes over time. This might allow interventional studies to test neuroprotective strategies (genetic or pharmacological) aimed at normalizing mitochondrial function in the presence of Parkin mutations, or in other genes that influence mitochondrial function.

最大的帕金突变携带者谱系（n=77）来自南蒂罗尔，包括许多帕金突变携带者的杂合携带者，他们表现出明显的帕金森氏病（PD）症状，而其他人可能有前驱症状，或没有明显的症状。我们的目标是剖析改变这些变异外显率的因素，使用南蒂罗尔合作健康研究（CHRIS）研究中的其他突变携带者（n=13,490来自同一地理区域）。在第一个资助期，测试影响线粒体功能的因素是否可以改变导致线粒体功能障碍的核突变的外显率，我们观察到，与非携带者相比，受影响的杂合Parkin和PINK1（磷酸酶和紧张素同源诱导的推定激酶1）突变携带者的mtDNA突变负担增加，这可能解释了表型(临床，这些核遗传背景相似的个体存在亚临床差异。然而，mtDNA变异作为外显率标记的特异性，以及mtDNA突变负荷增加最终导致神经退行性变的分子途径，需要用更大的数据集进一步研究。我们假设PD基因突变和线粒体功能之间存在外显子修饰的相互作用，受mtDNA突变负担和/或拷贝数的影响，通过涉及mtDNA维持的机制。在目标1中，我们将在CHRIS研究中识别额外的帕金突变携带者（预计总n=650），并对其前驱或显性PD的体征和症状进行表型表征。从一项成功的基因型召回试点研究中，我们建立了伦理框架，以召回携带者进行更深入的表型分析，并确定了在试点研究中能够区分携带者和非携带者的表型。在目标2中，我们将使用深度线粒体测序，确定目标1中鉴定的致病性帕金变异体携带者血液中的mtDNA突变负荷和破坏性mtDNA变异体。我们将测试这些变量是否会影响疾病外显率/表达性，并特别关注是否有可能检测到预测亚临床或临床表型出现的突变负担阈值。在目标3中，我们将在神经细胞模型中测试Parkin致病性变异、mtDNA突变和线粒体功能分子表型表达之间的因果关系，并测试在这种Parkin和mtDNA变异存在下可能挽救线粒体功能的机制。我们将描述在不同时间点从参与者身上提取的生物样本，以观察随时间的变化。这可能允许介入研究测试神经保护策略（遗传或药理学），旨在使帕金突变或其他影响线粒体功能的基因的线粒体功能正常化。