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The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP(+)-treated SH-SY5Y cells
Abnormal iron accumulation caused by elevated levels of divalent metal transporter 1 (DMT1) contributes to progressive neurodegeneration in Parkinson's disease (PD). Parkin is a E3 ubiquitin ligase for the ubiquitination of DMT1. S-nitrosylated parkin (SNO-parkin) is commonly observed in PD. Ho...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511936/ https://www.ncbi.nlm.nih.gov/pubmed/32968192 http://dx.doi.org/10.1038/s41598-020-72630-2 |
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author | Zhong, Yanmin Li, Xin Du, Xixun Bi, Mingxia Ma, Fengtong Xie, Junxia Jiang, Hong |
author_facet | Zhong, Yanmin Li, Xin Du, Xixun Bi, Mingxia Ma, Fengtong Xie, Junxia Jiang, Hong |
author_sort | Zhong, Yanmin |
collection | PubMed |
description | Abnormal iron accumulation caused by elevated levels of divalent metal transporter 1 (DMT1) contributes to progressive neurodegeneration in Parkinson's disease (PD). Parkin is a E3 ubiquitin ligase for the ubiquitination of DMT1. S-nitrosylated parkin (SNO-parkin) is commonly observed in PD. However, the effects of S-nitrosylation on the E3 ubiquitin ligase activity of parkin for the ubiquitination of DMT1 in PD are largely unknown. To elucidate the role of S-nitrosylated parkin and DMT1 in PD, SH-SY5Y cells were transfected with parkin, being treated with S-nitrosoglutathione (GSNO) and 1-methyl-4-phenylpyridinium (MPP(+)). The results showed increased levels of oxidized nitric oxide (NO) and S-nitrosylated parkin after the treatment of GSNO and MPP(+) in parkin-transfected cells. Consistently, increased levels of DMT1, iron uptake and cell viability were observed. Interestingly, inhibition of S-nitrosylated parkin reduced the level of DMT1. Further, S-nitrosylation of parkin significantly inhibited the ubiquitination of DMT1. When HEK293T cells were transfected with plasmid of parkin with single site mutation (Cys241A, Cys260A, Cys323A), ubiquitination of DMT1 was also inhibited. However, the cells cotransfected with plasmids containing all three mutations, GSNO treatment did not affect the ubiquitination of DMT1. The expression of SNO-parkin and DMT1 protein in substantia nigra increased significantly gradually after 2 h, 4 h and 24 h with MPTP injection. These results indicate that the S-nitrosylation of parkin inhibits its E3 ubiquitin ligase activity for the ubiquitination of DMT1, which contributes to iron accumulation and degenerative process in PD. Targeted S-nitrosylation could provide a potential therapeutic strategy against PD. |
format | Online Article Text |
id | pubmed-7511936 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75119362020-09-29 The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP(+)-treated SH-SY5Y cells Zhong, Yanmin Li, Xin Du, Xixun Bi, Mingxia Ma, Fengtong Xie, Junxia Jiang, Hong Sci Rep Article Abnormal iron accumulation caused by elevated levels of divalent metal transporter 1 (DMT1) contributes to progressive neurodegeneration in Parkinson's disease (PD). Parkin is a E3 ubiquitin ligase for the ubiquitination of DMT1. S-nitrosylated parkin (SNO-parkin) is commonly observed in PD. However, the effects of S-nitrosylation on the E3 ubiquitin ligase activity of parkin for the ubiquitination of DMT1 in PD are largely unknown. To elucidate the role of S-nitrosylated parkin and DMT1 in PD, SH-SY5Y cells were transfected with parkin, being treated with S-nitrosoglutathione (GSNO) and 1-methyl-4-phenylpyridinium (MPP(+)). The results showed increased levels of oxidized nitric oxide (NO) and S-nitrosylated parkin after the treatment of GSNO and MPP(+) in parkin-transfected cells. Consistently, increased levels of DMT1, iron uptake and cell viability were observed. Interestingly, inhibition of S-nitrosylated parkin reduced the level of DMT1. Further, S-nitrosylation of parkin significantly inhibited the ubiquitination of DMT1. When HEK293T cells were transfected with plasmid of parkin with single site mutation (Cys241A, Cys260A, Cys323A), ubiquitination of DMT1 was also inhibited. However, the cells cotransfected with plasmids containing all three mutations, GSNO treatment did not affect the ubiquitination of DMT1. The expression of SNO-parkin and DMT1 protein in substantia nigra increased significantly gradually after 2 h, 4 h and 24 h with MPTP injection. These results indicate that the S-nitrosylation of parkin inhibits its E3 ubiquitin ligase activity for the ubiquitination of DMT1, which contributes to iron accumulation and degenerative process in PD. Targeted S-nitrosylation could provide a potential therapeutic strategy against PD. Nature Publishing Group UK 2020-09-23 /pmc/articles/PMC7511936/ /pubmed/32968192 http://dx.doi.org/10.1038/s41598-020-72630-2 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Zhong, Yanmin Li, Xin Du, Xixun Bi, Mingxia Ma, Fengtong Xie, Junxia Jiang, Hong The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP(+)-treated SH-SY5Y cells |
title | The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP(+)-treated SH-SY5Y cells |
title_full | The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP(+)-treated SH-SY5Y cells |
title_fullStr | The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP(+)-treated SH-SY5Y cells |
title_full_unstemmed | The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP(+)-treated SH-SY5Y cells |
title_short | The S-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in MPP(+)-treated SH-SY5Y cells |
title_sort | s-nitrosylation of parkin attenuated the ubiquitination of divalent metal transporter 1 in mpp(+)-treated sh-sy5y cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511936/ https://www.ncbi.nlm.nih.gov/pubmed/32968192 http://dx.doi.org/10.1038/s41598-020-72630-2 |
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