Zhao Yibo, Bracher-Smith Matthew, Li Yuelin, Harvey Kirsten, Escott-Price Valentina, Lewis Patrick A, Manzoni Claudia
UCL School of Pharmacy, dept Pharmacology, London, UK.
University of Cardiff, School of Medicine, Division of Psychological Medicine and Clinical Neurosciences, Cardiff, UK.
NPJ Parkinsons Dis. 2024 Aug 3;10(1):144. doi: 10.1038/s41531-024-00761-8.
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.
LRRK2基因的突变是家族性帕金森病(LRRK2-PD)最常见的遗传病因,也是散发性帕金森病(sPD)的一个重要风险因素。目前正在进行多项临床试验,以评估降低LRRK2激酶活性治疗带来的益处。在本研究中,我们描述了sPD和LRRK2-PD患者中LRRK2蛋白相互作用分子的转录组图谱变化(全血mRNA水平),并与健康对照进行比较,目的是比较这两种帕金森病情况。我们接着构建了以LRRK2为中心的蛋白质-蛋白质相互作用(PPI)网络模型,该模型经过加权处理以反映LRRK2蛋白相互作用分子在表达和共表达水平上的转录组变化。我们的结果表明,LRRK2相互作用分子在sPD和LRRK2-PD患者中,在表达水平和共表达行为上呈现出相似和不同的变化;这表明,尽管基于临床特征被归类为同一种疾病,但从分子角度来看,LRRK2-PD和sPD存在显著差异。有趣的是,两种帕金森病情况下的相似变化导致与蛋白质代谢/生物合成以及核糖体代谢相关的LRRK2 PPI网络拓扑簇内的连通性降低,这表明与对照组相比,蛋白质稳态和核糖体动力学在散发性和家族性帕金森病中可能均受到影响。