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.

富含亮氨酸的重复激酶 2 (LRRK2) 是一种参与不同细胞功能的激酶，包括自噬、内溶酶体途径和免疫功能。LRRK2 的突变导致帕金森病 (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 的杂合突变是 PD 最常见的遗传风险因素。此外，GCase 功能在特发性 PD 和其他遗传形式的疾病中发生了改变。最近的工作表明 LRRK2 激酶活性可以调节 GCase 功能。然而，已经描述了正相关和负相关。为了深入了解 LRRK2 对 GCase 的影响，我们对互补 LRRK2 模型中的 GCase 水平和活性进行了全面分析，包括 (i) LRRK2 G2019S 敲入 (GSKI) 小鼠，(ii) 携带 LRRK2 G2019S 突变的 PD 患者的外周血单个核细胞 (PBMC)、血浆和成纤维细胞，(iii) 患者 iPSC 衍生的神经元；(iv) 内源性和过表达的细胞模型。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，这在具有 LRRK2 激酶活性的遗传和药理学操作的细胞系中得到了进一步证实。GCase 蛋白水平在 GSKI 脑组织和 G2019S iPSC 衍生的神经元中降低，但在患者的成纤维细胞和 PBMC 中增加，表明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，