Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression inH4, a Human Neuroglioma Cell Line Ruz, Clara Alcantud, José Luis Vives Montero, Francisco Arrebola Vargas, Francisco Jesús Durán Ogalla, Raquel LRRK2 Lysosomal dysfunction Glucocerebrosidase Parkinson's disease Autophagy 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 -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. 2022-09-05T07:45:24Z 2022-09-05T07:45:24Z 2022-06-22 journal article Ruz, C... [et al.]. Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression in H4, a Human Neuroglioma Cell Line. Int. J. Mol. Sci. 2022, 23, 6935. [https://doi.org/10.3390/ijms23136935] http://hdl.handle.net/10481/76497 10.3390/ijms23136935 eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional MDPI