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

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-Glucocerebrosidas...

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Autores principales: Ruz, Clara, Alcantud, José Luis, Vives, Francisco, Arrebola, Francisco, Hardy, John, Lewis, Patrick A., Manzoni, Claudia, Duran, Raquel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266636/
https://www.ncbi.nlm.nih.gov/pubmed/35805938
http://dx.doi.org/10.3390/ijms23136935
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author Ruz, Clara
Alcantud, José Luis
Vives, Francisco
Arrebola, Francisco
Hardy, John
Lewis, Patrick A.
Manzoni, Claudia
Duran, Raquel
author_facet Ruz, Clara
Alcantud, José Luis
Vives, Francisco
Arrebola, Francisco
Hardy, John
Lewis, Patrick A.
Manzoni, Claudia
Duran, Raquel
author_sort Ruz, Clara
collection PubMed
description 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.
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spelling pubmed-92666362022-07-09 Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression in H4, a Human Neuroglioma Cell Line Ruz, Clara Alcantud, José Luis Vives, Francisco Arrebola, Francisco Hardy, John Lewis, Patrick A. Manzoni, Claudia Duran, Raquel Int J Mol Sci Article 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. MDPI 2022-06-22 /pmc/articles/PMC9266636/ /pubmed/35805938 http://dx.doi.org/10.3390/ijms23136935 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ruz, Clara
Alcantud, José Luis
Vives, Francisco
Arrebola, Francisco
Hardy, John
Lewis, Patrick A.
Manzoni, Claudia
Duran, Raquel
Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression in H4, a Human Neuroglioma Cell Line
title Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression in H4, a Human Neuroglioma Cell Line
title_full Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression in H4, a Human Neuroglioma Cell Line
title_fullStr Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression in H4, a Human Neuroglioma Cell Line
title_full_unstemmed Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression in H4, a Human Neuroglioma Cell Line
title_short Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression in H4, a Human Neuroglioma Cell Line
title_sort seventy-two-hour lrrk2 kinase activity inhibition increases lysosomal gba expression in h4, a human neuroglioma cell line
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266636/
https://www.ncbi.nlm.nih.gov/pubmed/35805938
http://dx.doi.org/10.3390/ijms23136935
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