Abstract:
Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of dominantly inherited Parkinson\'s disease (PD). LRRK2 mutations, among which p.G2019S is the most frequent, are inherited with reduced penetrance. Interestingly, the disease risk associated with LRRK2 G2019S can vary dramatically depending on the ethnic background of the carrier. While this would suggest a genetic component in the definition of LRRK2-PD penetrance, only few variants have been shown to modify the age at onset of patients harbouring LRRK2 mutations, and the exact cellular pathways controlling the transition from a healthy to a diseased state currently remain elusive. In light of this knowledge gap, recent studies also explored environmental and lifestyle factors as potential modifiers of LRRK2-PD. In this article, we (i) describe the clinical characteristics of LRRK2 mutation carriers, (ii) review known genes linked to LRRK2-PD onset and (iii) summarize the cellular functions of LRRK2 with particular emphasis on potential penetrance-related molecular mechanisms. This section covers LRRK2\'s involvement in Rab GTPase and immune signalling as well as in the regulation of mitochondrial homeostasis and dynamics. Additionally, we explored the literature with regard to (iv) lifestyle and (v) environmental factors that may influence the penetrance of LRRK2 mutations, with a view towards further exposomics studies. Finally, based on this comprehensive overview, we propose potential future in vivo, in vitro and in silico studies that could provide a better understanding of the processes triggering PD in individuals with LRRK2 mutations.
摘要:
富含亮氨酸的重复激酶2(LRRK2)的突变是显性遗传性帕金森病(PD)的最常见原因。LRRK2突变,其中P.G2019S是最常见的,以降低的外显率遗传。有趣的是,与LRRK2G2019S相关的疾病风险可根据携带者的种族背景而显著变化.虽然这表明LRRK2-PD外显率定义中存在遗传成分,只有少数变异被证明能改变LRRK2突变患者的发病年龄,控制从健康状态到疾病状态转变的确切细胞途径目前仍然难以捉摸。鉴于这种知识差距,最近的研究还探索了环境和生活方式因素作为LRRK2-PD的潜在修饰剂。在这篇文章中,我们(i)描述了LRRK2突变携带者的临床特征,(ii)回顾与LRRK2-PD发病相关的已知基因,(iii)总结LRRK2的细胞功能,特别强调潜在的外显率相关分子机制。本节涵盖LRRK2参与RabGTP酶和免疫信号以及线粒体稳态和动力学的调节。此外,我们探索了有关(iv)生活方式和(v)可能影响LRRK2突变外显率的环境因素的文献,以期进一步进行暴露组学研究。最后,基于这个全面的概述,我们提出了体内潜在的未来,体外和计算机模拟研究可以更好地了解LRRK2突变个体中触发PD的过程。