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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...

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Autores principales: Ma, Jianjun, Li, Xiaohuan, Fan, Yongyan, Yang, Dawei, Gu, Qi, Li, Dongsheng, Chen, Siyuan, Wu, Shaopu, Zheng, Jinhua, Yang, Hongqi, Li, Xue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2022
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.
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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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