Effect of LRRK2 Inhibition on the Activity of Glucocerebrosidase in Patient-Specific Cells from Patients with Gaucher Disease.

Biallelic mutations in the GBA1 gene encoding lysosomal enzyme glucocerebrosidase (GCase), lead to the development of the Gaucher disease (GD) and also represent a significant risk factor for the Parkinson's disease (PD). In most cases, mutations in the GBA1 gene are located outside the region coding for the enzyme active site and cause a decrease in the GCase activity due to the reduction in the efficiency of transport of conformationally altered enzyme to the lysosomes. Drugs used to treat GD (enzyme replacement therapy) cannot cross the blood-brain barrier and, therefore, are not effective in the treatment of neuronal forms of GD or PD associated with mutations in the GBA1 gene (GBA1-PD). Currently, inhibitors of the leucine-rich repeat kinase 2 (LRRK2) are undergoing clinical trials for the treatment of PD. It was previously shown that inhibition of LRRK2 leads to the increase in the GCase activity in patient-specific GBA1-PD cells. We assessed the effect of the LRRK2 inhibitor MLi-2 on the GCase activity in the primary culture of peripheral blood macrophages from patients with type 1 GD. The activity of GCase and the levels of its substrate in cells cultured with and without MLi-2 was assayed by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). No effect of LRRK2 inhibition on the activity GCase in a group of patients with GD was found.