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LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells

BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the pathogenesis of Parkinson's disease (PD). Aging is the most critical risk factor for the progression of PD. The correlation between aging and cellular senescence has been established. Cellular senescence is correlated...

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Autores principales: Ho, Dong Hwan, Nam, Daleum, Seo, Mi Kyoung, Park, Sung Woo, Seol, Wongi, Son, Ilhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282384/
https://www.ncbi.nlm.nih.gov/pubmed/34306319
http://dx.doi.org/10.1155/2021/9969842
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author Ho, Dong Hwan
Nam, Daleum
Seo, Mi Kyoung
Park, Sung Woo
Seol, Wongi
Son, Ilhong
author_facet Ho, Dong Hwan
Nam, Daleum
Seo, Mi Kyoung
Park, Sung Woo
Seol, Wongi
Son, Ilhong
author_sort Ho, Dong Hwan
collection PubMed
description BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the pathogenesis of Parkinson's disease (PD). Aging is the most critical risk factor for the progression of PD. The correlation between aging and cellular senescence has been established. Cellular senescence is correlated with the dysregulation of the proteolytic pathway and mitochondrial dysfunction, which are also associated with the aggregation of α-synuclein (α-syn). METHODS: Human dopaminergic neuron-like cells (differentiated SH-SY5Y cells) were treated with rotenone in the presence or absence of the LRRK2 kinase inhibitor GSK2578215A (GSK-KI) for 48 h. The markers of cellular senescence, including p53, p21(Waf1/Cip1) (p21), β-galactosidase (β-gal), Rb phosphorylation, senescence-associated (SA) β-gal activity, and lysosomal activity, were examined. The dSH cells and rat primary cortical neurons were treated with α-syn fibrils 30 min before treatment with rotenone in the presence or absence of GSK-KI for 48 h. Mice were intraperitoneally injected with rotenone and MLi-2 (LRRK2 kinase inhibitor) once every two days for two weeks. RESULTS: Rotenone upregulated LRRK2 phosphorylation and β-gal levels through the activation of the p53-p21 signaling axis and downregulated Rb phosphorylation. Additionally, rotenone upregulated SA β-gal activity, reactive oxygen species levels, and LRRK2 phosphorylation and inhibited lysosome activity. Rotenone-induced LRRK2 upregulation impaired the clearance of α-syn fibrils. Treatment with LRRK2 inhibitor mitigated rotenone-induced cellular senescence and α-syn accumulation. CONCLUSIONS: Rotenone-induced upregulation of LRRK2 kinase activity promoted cellular senescence, which enhanced α-syn accumulation. However, the administration of an LRRK2 kinase inhibitor rejuvenated rotenone-induced cellular senescence.
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spelling pubmed-82823842021-07-22 LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells Ho, Dong Hwan Nam, Daleum Seo, Mi Kyoung Park, Sung Woo Seol, Wongi Son, Ilhong Oxid Med Cell Longev Research Article BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the pathogenesis of Parkinson's disease (PD). Aging is the most critical risk factor for the progression of PD. The correlation between aging and cellular senescence has been established. Cellular senescence is correlated with the dysregulation of the proteolytic pathway and mitochondrial dysfunction, which are also associated with the aggregation of α-synuclein (α-syn). METHODS: Human dopaminergic neuron-like cells (differentiated SH-SY5Y cells) were treated with rotenone in the presence or absence of the LRRK2 kinase inhibitor GSK2578215A (GSK-KI) for 48 h. The markers of cellular senescence, including p53, p21(Waf1/Cip1) (p21), β-galactosidase (β-gal), Rb phosphorylation, senescence-associated (SA) β-gal activity, and lysosomal activity, were examined. The dSH cells and rat primary cortical neurons were treated with α-syn fibrils 30 min before treatment with rotenone in the presence or absence of GSK-KI for 48 h. Mice were intraperitoneally injected with rotenone and MLi-2 (LRRK2 kinase inhibitor) once every two days for two weeks. RESULTS: Rotenone upregulated LRRK2 phosphorylation and β-gal levels through the activation of the p53-p21 signaling axis and downregulated Rb phosphorylation. Additionally, rotenone upregulated SA β-gal activity, reactive oxygen species levels, and LRRK2 phosphorylation and inhibited lysosome activity. Rotenone-induced LRRK2 upregulation impaired the clearance of α-syn fibrils. Treatment with LRRK2 inhibitor mitigated rotenone-induced cellular senescence and α-syn accumulation. CONCLUSIONS: Rotenone-induced upregulation of LRRK2 kinase activity promoted cellular senescence, which enhanced α-syn accumulation. However, the administration of an LRRK2 kinase inhibitor rejuvenated rotenone-induced cellular senescence. Hindawi 2021-07-08 /pmc/articles/PMC8282384/ /pubmed/34306319 http://dx.doi.org/10.1155/2021/9969842 Text en Copyright © 2021 Dong Hwan Ho et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Ho, Dong Hwan
Nam, Daleum
Seo, Mi Kyoung
Park, Sung Woo
Seol, Wongi
Son, Ilhong
LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells
title LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells
title_full LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells
title_fullStr LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells
title_full_unstemmed LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells
title_short LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells
title_sort lrrk2 kinase inhibitor rejuvenates oxidative stress-induced cellular senescence in neuronal cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282384/
https://www.ncbi.nlm.nih.gov/pubmed/34306319
http://dx.doi.org/10.1155/2021/9969842
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