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The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson’s Disease Model
The pathogenesis of Parkinson’s disease (PD) is very complex and still needs further exploration. Leucine-rich repeat kinase 2 (LRRK2) is associated with familial PD in mutant forms and sporadic PD in the wild-type form. Abnormal iron accumulation is found in the substantia nigra of PD patients, but...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9964371/ https://www.ncbi.nlm.nih.gov/pubmed/36835121 http://dx.doi.org/10.3390/ijms24043709 |
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author | Jia, Ruru Liu, Yanling Shuai, Ke Zhou, Cheng Chen, Lei Zhu, Li Wu, Xiao-Mei |
author_facet | Jia, Ruru Liu, Yanling Shuai, Ke Zhou, Cheng Chen, Lei Zhu, Li Wu, Xiao-Mei |
author_sort | Jia, Ruru |
collection | PubMed |
description | The pathogenesis of Parkinson’s disease (PD) is very complex and still needs further exploration. Leucine-rich repeat kinase 2 (LRRK2) is associated with familial PD in mutant forms and sporadic PD in the wild-type form. Abnormal iron accumulation is found in the substantia nigra of PD patients, but its exact effects are not very clear. Here, we show that iron dextran exacerbates the neurological deficit and loss of dopaminergic neurons in 6-OHDA lesioned rats. 6-OHDA and ferric ammonium citrate (FAC) significantly increase the activity of LRRK2 as reflected by the phosphorylation of LRRK2, at S935 and S1292 sites. 6-OHDA-induced LRRK2 phosphorylation is attenuated by the iron chelator deferoxamine, especially at the S1292 site. 6-OHDA and FAC markedly induce the expression of pro-apoptotic molecules and the production of ROS by activating LRRK2. Furthermore, G2019S-LRRK2 with high kinase activity showed the strongest absorptive capacity for ferrous iron and the highest intracellular iron content among WT-LRRK2, G2019S-LRRK2, and kinase-inactive D2017A-LRRK2 groups. Taken together, our results demonstrate that iron promotes the activation of LRRK2, and active LRRK2 accelerates ferrous iron uptake, suggesting that there exists an interplay between iron and LRRK2 in dopaminergic neurons, providing a new perspective to uncover the underlying mechanisms of PD occurrence. |
format | Online Article Text |
id | pubmed-9964371 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99643712023-02-26 The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson’s Disease Model Jia, Ruru Liu, Yanling Shuai, Ke Zhou, Cheng Chen, Lei Zhu, Li Wu, Xiao-Mei Int J Mol Sci Article The pathogenesis of Parkinson’s disease (PD) is very complex and still needs further exploration. Leucine-rich repeat kinase 2 (LRRK2) is associated with familial PD in mutant forms and sporadic PD in the wild-type form. Abnormal iron accumulation is found in the substantia nigra of PD patients, but its exact effects are not very clear. Here, we show that iron dextran exacerbates the neurological deficit and loss of dopaminergic neurons in 6-OHDA lesioned rats. 6-OHDA and ferric ammonium citrate (FAC) significantly increase the activity of LRRK2 as reflected by the phosphorylation of LRRK2, at S935 and S1292 sites. 6-OHDA-induced LRRK2 phosphorylation is attenuated by the iron chelator deferoxamine, especially at the S1292 site. 6-OHDA and FAC markedly induce the expression of pro-apoptotic molecules and the production of ROS by activating LRRK2. Furthermore, G2019S-LRRK2 with high kinase activity showed the strongest absorptive capacity for ferrous iron and the highest intracellular iron content among WT-LRRK2, G2019S-LRRK2, and kinase-inactive D2017A-LRRK2 groups. Taken together, our results demonstrate that iron promotes the activation of LRRK2, and active LRRK2 accelerates ferrous iron uptake, suggesting that there exists an interplay between iron and LRRK2 in dopaminergic neurons, providing a new perspective to uncover the underlying mechanisms of PD occurrence. MDPI 2023-02-13 /pmc/articles/PMC9964371/ /pubmed/36835121 http://dx.doi.org/10.3390/ijms24043709 Text en © 2023 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 Jia, Ruru Liu, Yanling Shuai, Ke Zhou, Cheng Chen, Lei Zhu, Li Wu, Xiao-Mei The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson’s Disease Model |
title | The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson’s Disease Model |
title_full | The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson’s Disease Model |
title_fullStr | The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson’s Disease Model |
title_full_unstemmed | The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson’s Disease Model |
title_short | The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson’s Disease Model |
title_sort | relationship between iron and lrrk2 in a 6-ohda-induced parkinson’s disease model |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9964371/ https://www.ncbi.nlm.nih.gov/pubmed/36835121 http://dx.doi.org/10.3390/ijms24043709 |
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