Charles Perkins Centre and Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Camperdown, NSW 2050, Australia.
Brain and Mind Centre and Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Camperdown, NSW 2050, Australia.
Biomolecules. 2022 Oct 30;12(11):1597. doi: 10.3390/biom12111597.
Genetic alterations in the gene, encoding leucine-rich repeat kinase 2, are a common risk factor for Parkinson's disease. How LRRK2 alterations lead to cell pathology is an area of ongoing investigation, however, multiple lines of evidence suggest a role for LRRK2 in lipid pathways. It is increasingly recognized that in addition to being energy reservoirs and structural entities, some lipids, including neural lipids, participate in signaling cascades. Early investigations revealed that LRRK2 localized to membranous and vesicular structures, suggesting an interaction of LRRK2 and lipids or lipid-associated proteins. LRRK2 substrates from the Rab GTPase family play a critical role in vesicle trafficking, lipid metabolism and lipid storage, all processes which rely on lipid dynamics. In addition, LRRK2 is associated with the phosphorylation and activity of enzymes that catabolize plasma membrane and lysosomal lipids. Furthermore, LRRK2 knockout studies have revealed that blood, brain and urine exhibit lipid level changes, including alterations to sterols, sphingolipids and phospholipids, respectively. In human LRRK2 mutation carriers, changes to sterols, sphingolipids, phospholipids, fatty acyls and glycerolipids are reported in multiple tissues. This review summarizes the evidence regarding associations between LRRK2 and lipids, and the functional consequences of LRRK2-associated lipid changes are discussed.
基因中的遗传改变，编码富含亮氨酸重复激酶 2，是帕金森病的一个常见危险因素。LRRK2 改变如何导致细胞病理学是一个正在进行的研究领域，然而，多条证据表明 LRRK2 在脂质途径中起作用。人们越来越认识到，除了作为能量储备和结构实体外，一些脂质，包括神经脂质，参与信号级联反应。早期的研究表明，LRRK2 定位于膜和囊泡结构，提示 LRRK2 与脂质或脂质相关蛋白相互作用。Rab GTPase 家族的 LRRK2 底物在囊泡运输、脂质代谢和脂质储存中发挥关键作用，所有这些过程都依赖于脂质动力学。此外，LRRK2 与分解质膜和溶酶体脂质的酶的磷酸化和活性有关。此外，LRRK2 敲除研究表明，血液、大脑和尿液显示脂质水平变化，分别包括固醇、鞘脂和磷脂的改变。在人类 LRRK2 突变携带者中，在多种组织中报告了固醇、鞘脂、磷脂、脂肪酸和甘油脂质的改变。本综述总结了 LRRK2 与脂质之间的关联的证据，并讨论了与 LRRK2 相关的脂质变化的功能后果。
