Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression in H4, a Human Neuroglioma Cell Line

Abstract

Mutations in LRRK2 and GBA1 are key contributors to genetic risk of developing Parkinson’s disease (PD). To investigate how LRRK2 kinase activity interacts with GBA and contributes to lysosomal dysfunctions associated with the pathology of PD. The activity of the lysosomal enzyme β-Glucocerebrosidase (GCase) was assessed in a human neuroglioma cell model treated with two selective inhibitors of LRKK2 kinase activity (LRRK2-in-1 and MLi-2) and a GCase irreversible inhibitor, condutirol-beta-epoxide (CBE), under 24 and 72 h experimental conditions. We observed levels of GCase activity comparable to controls in response to 24 and 72 h treatments with LRRK2-in-1 and MLi-2. However, GBA protein levels increased upon 72 h treatment with LRRK2-in-1. Moreover, LC3-II protein levels were increased after both 24 and 72 h treatments with LRRK2-in-1, suggesting an activation of the autophagic pathway. These results highlight a possible regulation of lysosomal function through the LRRK2 kinase domain and suggest an interplay between LRRK2 kinase activity and GBA. Although further investigations are needed, the enhancement of GCase activity might restore the defective protein metabolism seen in PD.

Molecular Mechanisms Underlying Chronic and Degenerative Diseases

“…For their part, Ruz et al [4], in their original research article, analyze the mechanisms involved in the pathogenesis of Parkinson's disease (PD). PD is an age-related chronic neurodegenerative disorder, and decades of research, among other risk factors, have established the importance of rare and common genetic variants.…”

“…Notably, mutations in LRRK2 or GBA1 genes or alterations in their enzymatic activities are well-recognized contributors to PD pathogenesis, but despite this, the specific mechanistic interplay between these two molecules remains undetermined. In this sense, Ruz and colleagues [4] reported that the inhibition of LRRK2 kinase activity in a human neuroglioma cell model resulted in increased GBA protein levels with no changes in the overall GCase activity compared to the control cells. This study suggests a possible regulation of lysosomal function through LRRK2 and supports an interplay between LRRK2 kinase activity and GBA.…”