npj Parkinson's Disease ( IF 6.7 ) Pub Date : 2024-08-03 , DOI: 10.1038/s41531-024-00761-8 Yibo Zhao 1 , Matthew Bracher-Smith 2, 3 , Yuelin Li 1 , Kirsten Harvey 1 , Valentina Escott-Price 2, 3 , Patrick A Lewis 4, 5 , Claudia Manzoni 1
Mutations in the LRRK2 gene are the most common genetic cause of familial Parkinson’s Disease (LRRK2-PD) and an important risk factor for sporadic PD (sPD). Multiple clinical trials are ongoing to evaluate the benefits associated with the therapeutical reduction of LRRK2 kinase activity. In this study, we described the changes of transcriptomic profiles (whole blood mRNA levels) of LRRK2 protein interactors in sPD and LRRK2-PD cases as compared to healthy controls with the aim of comparing the two PD conditions. We went on to model the protein-protein interaction (PPI) network centred on LRRK2, which was weighted to reflect the transcriptomic changes on expression and co-expression levels of LRRK2 protein interactors. Our results showed that LRRK2 interactors present both similar and distinct alterations in expression levels and co-expression behaviours in the sPD and LRRK2-PD cases; suggesting that, albeit being classified as the same disease based on clinical features, LRRK2-PD and sPD display significant differences from a molecular perspective. Interestingly, the similar changes across the two PD conditions result in decreased connectivity within a topological cluster of the LRRK2 PPI network associated with protein metabolism/biosynthesis and ribosomal metabolism suggesting protein homoeostasis and ribosomal dynamics might be affected in both sporadic and familial PD in comparison with controls.
中文翻译:
LRRK2 蛋白相互作用组的转录组学和加权蛋白质网络分析揭示了散发性和 LRRK2 帕金森病的不同分子特征
LRRK2 基因突变是家族性帕金森病 (LRRK2-PD) 最常见的遗传原因,也是散发性帕金森病 (sPD) 的重要危险因素。多项临床试验正在进行中,以评估与治疗性降低 LRRK2 激酶活性相关的益处。在这项研究中,我们描述了与健康对照相比,sPD 和 LRRK2-PD 病例中 LRRK2 蛋白相互作用物的转录组谱 (全血 mRNA 水平) 的变化,目的是比较两种 PD 条件。我们继续对以 LRRK2 为中心的蛋白质-蛋白质相互作用 (PPI) 网络进行建模,该网络被加权以反映 LRRK2 蛋白相互作用物表达和共表达水平的转录组变化。我们的结果表明,在 sPD 和 LRRK2-PD 病例中,LRRK2 相互作用子在表达水平和共表达行为方面表现出相似和不同的改变;这表明,尽管根据临床特征被归类为同一疾病,但从分子角度来看,LRRK2-PD 和 sPD 表现出显着差异。有趣的是,两种 PD 条件的相似变化导致与蛋白质代谢/生物合成和核糖体代谢相关的 LRRK2 PPI 网络拓扑簇内的连接性降低,这表明与对照组相比,散发性和家族性 PD 中的蛋白质稳态和核糖体动力学可能受到影响。