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miR-494-3p Promotes Erastin-Induced Ferroptosis by Targeting REST to Activate the Interplay between SP1 and ACSL4 in Parkinson's Disease
BACKGROUND: Ferroptosis is a type of iron-dependent programmed cell death. Ferroptosis has been shown to be a significant factor for the pathogenesis of Parkinson's disease (PD). However, the mechanism involved in ferroptosis has not been fully elucidated in PD. METHODS: Repressor element-1 sil...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9355771/ https://www.ncbi.nlm.nih.gov/pubmed/35936219 http://dx.doi.org/10.1155/2022/7671324 |
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author | Ma, Jianjun Li, Xiaohuan Fan, Yongyan Yang, Dawei Gu, Qi Li, Dongsheng Chen, Siyuan Wu, Shaopu Zheng, Jinhua Yang, Hongqi Li, Xue |
author_facet | Ma, Jianjun Li, Xiaohuan Fan, Yongyan Yang, Dawei Gu, Qi Li, Dongsheng Chen, Siyuan Wu, Shaopu Zheng, Jinhua Yang, Hongqi Li, Xue |
author_sort | Ma, Jianjun |
collection | PubMed |
description | BACKGROUND: Ferroptosis is a type of iron-dependent programmed cell death. Ferroptosis has been shown to be a significant factor for the pathogenesis of Parkinson's disease (PD). However, the mechanism involved in ferroptosis has not been fully elucidated in PD. METHODS: Repressor element-1 silencing transcription factor (REST) and specificity protein 1 (SP1) expressions were monitored by qRT-PCR. Cell viability, reactive oxygen species (ROS), and mitochondrial injury were validated by CCK-8, flow cytometry, and transmission electron microscope. The levels of neurons-related proteins and ferroptosis-associated proteins were identified by western blot and immunofluorescence assays. The interaction between miR-494-3p and REST or SP1 and ACSL4 was analyzed by luciferase, chromatin immunoprecipitation, or EMSA assay. RESULTS: Erastin could dose-dependently induce neuron injury and ferroptosis of LUHMES cells. miR-494-3p overexpression induced ROS production, mitochondrial damage, ferroptosis, and neuron injury in erastin-induced LUHMES cells. Likewise, miR-494-3p inhibition had the opposite effects. We also showed that REST was a target gene of miR-494-3p and could repress erastin-induced ferroptosis, neuron injury, ROS, and mitochondrial injury via SP1 in LUHMES cells. Moreover, we demonstrated that SP1 could interact with ACSL4. We also confirmed that miR-494-3p could aggravate the pathological changes of substantia nigra and corpus striatum in the MPTP-induced PD mouse model. CONCLUSION: miR-494-3p significantly promotes ferroptosis by regulating the REST/SP1/ACSL4 axis in PD. Thus, our results open potential therapeutic targets for PD. |
format | Online Article Text |
id | pubmed-9355771 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-93557712022-08-06 miR-494-3p Promotes Erastin-Induced Ferroptosis by Targeting REST to Activate the Interplay between SP1 and ACSL4 in Parkinson's Disease Ma, Jianjun Li, Xiaohuan Fan, Yongyan Yang, Dawei Gu, Qi Li, Dongsheng Chen, Siyuan Wu, Shaopu Zheng, Jinhua Yang, Hongqi Li, Xue Oxid Med Cell Longev Research Article BACKGROUND: Ferroptosis is a type of iron-dependent programmed cell death. Ferroptosis has been shown to be a significant factor for the pathogenesis of Parkinson's disease (PD). However, the mechanism involved in ferroptosis has not been fully elucidated in PD. METHODS: Repressor element-1 silencing transcription factor (REST) and specificity protein 1 (SP1) expressions were monitored by qRT-PCR. Cell viability, reactive oxygen species (ROS), and mitochondrial injury were validated by CCK-8, flow cytometry, and transmission electron microscope. The levels of neurons-related proteins and ferroptosis-associated proteins were identified by western blot and immunofluorescence assays. The interaction between miR-494-3p and REST or SP1 and ACSL4 was analyzed by luciferase, chromatin immunoprecipitation, or EMSA assay. RESULTS: Erastin could dose-dependently induce neuron injury and ferroptosis of LUHMES cells. miR-494-3p overexpression induced ROS production, mitochondrial damage, ferroptosis, and neuron injury in erastin-induced LUHMES cells. Likewise, miR-494-3p inhibition had the opposite effects. We also showed that REST was a target gene of miR-494-3p and could repress erastin-induced ferroptosis, neuron injury, ROS, and mitochondrial injury via SP1 in LUHMES cells. Moreover, we demonstrated that SP1 could interact with ACSL4. We also confirmed that miR-494-3p could aggravate the pathological changes of substantia nigra and corpus striatum in the MPTP-induced PD mouse model. CONCLUSION: miR-494-3p significantly promotes ferroptosis by regulating the REST/SP1/ACSL4 axis in PD. Thus, our results open potential therapeutic targets for PD. Hindawi 2022-07-29 /pmc/articles/PMC9355771/ /pubmed/35936219 http://dx.doi.org/10.1155/2022/7671324 Text en Copyright © 2022 Jianjun Ma 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 Ma, Jianjun Li, Xiaohuan Fan, Yongyan Yang, Dawei Gu, Qi Li, Dongsheng Chen, Siyuan Wu, Shaopu Zheng, Jinhua Yang, Hongqi Li, Xue miR-494-3p Promotes Erastin-Induced Ferroptosis by Targeting REST to Activate the Interplay between SP1 and ACSL4 in Parkinson's Disease |
title | miR-494-3p Promotes Erastin-Induced Ferroptosis by Targeting REST to Activate the Interplay between SP1 and ACSL4 in Parkinson's Disease |
title_full | miR-494-3p Promotes Erastin-Induced Ferroptosis by Targeting REST to Activate the Interplay between SP1 and ACSL4 in Parkinson's Disease |
title_fullStr | miR-494-3p Promotes Erastin-Induced Ferroptosis by Targeting REST to Activate the Interplay between SP1 and ACSL4 in Parkinson's Disease |
title_full_unstemmed | miR-494-3p Promotes Erastin-Induced Ferroptosis by Targeting REST to Activate the Interplay between SP1 and ACSL4 in Parkinson's Disease |
title_short | miR-494-3p Promotes Erastin-Induced Ferroptosis by Targeting REST to Activate the Interplay between SP1 and ACSL4 in Parkinson's Disease |
title_sort | mir-494-3p promotes erastin-induced ferroptosis by targeting rest to activate the interplay between sp1 and acsl4 in parkinson's disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9355771/ https://www.ncbi.nlm.nih.gov/pubmed/35936219 http://dx.doi.org/10.1155/2022/7671324 |
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