Kedariti Maria, Frattini Emanuele, Baden Pascale, Cogo Susanna, Civiero Laura, Ziviani Elena, Zilio Gianluca, Bertoli Federico, Aureli Massimo, Kaganovich Alice, Cookson Mark R, Stefanis Leonidas, Surface Matthew, Deleidi Michela, Di Fonzo Alessio, Alcalay Roy N, Rideout Hardy, Greggio Elisa, Plotegher Nicoletta
Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
NPJ Parkinsons Dis. 2022 Jul 19;8(1):92. doi: 10.1038/s41531-022-00354-3.
Leucine-rich repeat kinase 2 (LRRK2) is a kinase involved in different cellular functions, including autophagy, endolysosomal pathways, and immune function. Mutations in LRRK2 cause autosomal-dominant forms of Parkinson's disease (PD). Heterozygous mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), are the most common genetic risk factors for PD. Moreover, GCase function is altered in idiopathic PD and in other genetic forms of the disease. Recent work suggests that LRRK2 kinase activity can regulate GCase function. However, both a positive and a negative correlation have been described. To gain insights into the impact of LRRK2 on GCase, we performed a comprehensive analysis of GCase levels and activity in complementary LRRK2 models, including (i) LRRK2 G2019S knock in (GSKI) mice, (ii) peripheral blood mononuclear cell (PBMCs), plasma, and fibroblasts from PD patients carrying LRRK2 G2019S mutation, (iii) patient iPSCs-derived neurons; (iv) endogenous and overexpressed cell models. In some of these models we found a positive correlation between the activities of LRRK2 and GCase, which was further confirmed in cell lines with genetic and pharmacological manipulation of LRRK2 kinase activity. GCase protein level is reduced in GSKI brain tissues and in G2019S iPSCs-derived neurons, but increased in fibroblasts and PBMCs from patients, suggesting cell-type-specific effects. Overall, our study indicates that LRRK2 kinase activity affects both the levels and the catalytic activity of GCase in a cell-type-specific manner, with important implications in the context of therapeutic application of LRRK2 inhibitors in GBA1-linked and idiopathic PD.
富含亮氨酸重复序列激酶2（LRRK2）是一种参与多种细胞功能的激酶，包括自噬、内吞溶酶体途径和免疫功能。LRRK2突变会导致帕金森病（PD）的常染色体显性遗传形式。编码溶酶体酶葡萄糖脑苷脂酶（GCase）的基因GBA1中的杂合突变是PD最常见的遗传风险因素。此外，在特发性PD和该疾病的其他遗传形式中，GCase功能也会发生改变。最近的研究表明，LRRK2激酶活性可以调节GCase功能。然而，已有研究描述了两者之间存在正相关和负相关。为了深入了解LRRK2对GCase的影响，我们在互补的LRRK2模型中对GCase水平和活性进行了全面分析，这些模型包括：（i）LRRK2 G2019S基因敲入（GSKI）小鼠；（ii）携带LRRK2 G2019S突变的PD患者的外周血单核细胞（PBMC）、血浆和成纤维细胞；（iii）患者诱导多能干细胞（iPSC）衍生的神经元；（iv）内源性和过表达细胞模型。在其中一些模型中，我们发现LRRK2和GCase的活性之间存在正相关，这在对LRRK2激酶活性进行遗传和药理学操作的细胞系中得到了进一步证实。GSKI脑组织和G2019S iPSC衍生的神经元中GCase蛋白水平降低，但患者的成纤维细胞和PBMC中GCase蛋白水平升高，表明存在细胞类型特异性效应。总体而言，我们的研究表明，LRRK2激酶活性以细胞类型特异性方式影响GCase的水平和催化活性，这对于LRRK2抑制剂在GBA1相关和特发性PD治疗应用中的意义重大。
