Evaluation of the effect of inhibition of LRRK2 kinase activity on glucocerebrosidase activity on patient-specific cells from patients with Gaucher disease

Biallelic mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), lead to the development of a lysosomal storage disease, Gaucher disease (GD), and are also a high risk factor for a common neurodegenerative disease, Parkinson’s disease (PD). In most cases, mutations in the GBA1 gene are localized outside the active site and lead to a decrease in GCase activity due to a decrease in the efficiency of transport of the enzyme with an altered conformation into the lysosome. Drugs that are used to treat GD (enzyme replacement therapy) are not able to cross the blood-brain barrier and are not effective for the treatment of neuronal forms of GD or PD associated with mutations in the GBA1 gene (GBA1-PD). For the treatment of PD, drugs that inhibit the kinase activity of leucine-rich repeat kinase 2 (LRRK2) are currently undergoing clinical trials. It was previously shown that inhibition of LRRK2 kinase activity leads to an increase in GCase activity in patient-specific GBA1-PD cells. We first assessed the effect of the kinase activity inhibitor LRRK2 (MLi-2) on GCase activity in a primary culture of peripheral blood macrophages obtained from patients with type 1 GD. Assessment of GCase activity and its substrate levels in cells cultured with and without MLi-2 was performed using high-performance liquid chromatography coupled with tandem mass spectrometry. There was no effect of inhibition of LRRK2 activity on GCase activity in the group of patients with GD.