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Deubiquitylase OTUD3 prevents Parkinson’s disease through stabilizing iron regulatory protein 2
Iron deposits are neuropathological hallmark of Parkinson’s disease (PD). Iron regulatory protein 2 (IRP2) is a key factor in regulating brain iron homeostasis. Although two ubiquitin ligases that promote IRP2 degradation have been identified, the deubiquitylase for stabilization of IRP2 in PD remai...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9056525/ https://www.ncbi.nlm.nih.gov/pubmed/35490179 http://dx.doi.org/10.1038/s41419-022-04704-0 |
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author | Jia, Fengju Li, Hongchang Jiao, Qian Li, Chaonan Fu, Lin Cui, Chunping Jiang, Hong Zhang, Lingqiang |
author_facet | Jia, Fengju Li, Hongchang Jiao, Qian Li, Chaonan Fu, Lin Cui, Chunping Jiang, Hong Zhang, Lingqiang |
author_sort | Jia, Fengju |
collection | PubMed |
description | Iron deposits are neuropathological hallmark of Parkinson’s disease (PD). Iron regulatory protein 2 (IRP2) is a key factor in regulating brain iron homeostasis. Although two ubiquitin ligases that promote IRP2 degradation have been identified, the deubiquitylase for stabilization of IRP2 in PD remains undefined. Here, we report OTUD3 (OTU domain-containing protein 3) functions as a deubiquitylase for IRP2, interacts with IRP2 in the cytoplasm, de-polyubiquitylates, and stabilizes IRP2 protein in an iron-independent manner. Depletion of OTUD3 results in a disorder of iron metabolism. OTUD3 knockout mice display nigral iron accumulation, motor deficits, and nigrostriatal dopaminergic neurodegeneration, which resembles the pathology of PD. Consistently, decreased levels of OTUD3 are detected in transgenic PD mice expressing A53T mutant of human α-synuclein. Five single nucleotide polymorphism mutations of OTUD3 are present in cases of sporadic PD or controls, although no significant associations of OTUD3 SNPs with sporadic PD are detected. Taken together, these findings demonstrate that OTUD3 is a bona fide deubiquitylase for IRP2 and plays a critical role in the nigral iron deposits in PD. |
format | Online Article Text |
id | pubmed-9056525 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90565252022-05-02 Deubiquitylase OTUD3 prevents Parkinson’s disease through stabilizing iron regulatory protein 2 Jia, Fengju Li, Hongchang Jiao, Qian Li, Chaonan Fu, Lin Cui, Chunping Jiang, Hong Zhang, Lingqiang Cell Death Dis Article Iron deposits are neuropathological hallmark of Parkinson’s disease (PD). Iron regulatory protein 2 (IRP2) is a key factor in regulating brain iron homeostasis. Although two ubiquitin ligases that promote IRP2 degradation have been identified, the deubiquitylase for stabilization of IRP2 in PD remains undefined. Here, we report OTUD3 (OTU domain-containing protein 3) functions as a deubiquitylase for IRP2, interacts with IRP2 in the cytoplasm, de-polyubiquitylates, and stabilizes IRP2 protein in an iron-independent manner. Depletion of OTUD3 results in a disorder of iron metabolism. OTUD3 knockout mice display nigral iron accumulation, motor deficits, and nigrostriatal dopaminergic neurodegeneration, which resembles the pathology of PD. Consistently, decreased levels of OTUD3 are detected in transgenic PD mice expressing A53T mutant of human α-synuclein. Five single nucleotide polymorphism mutations of OTUD3 are present in cases of sporadic PD or controls, although no significant associations of OTUD3 SNPs with sporadic PD are detected. Taken together, these findings demonstrate that OTUD3 is a bona fide deubiquitylase for IRP2 and plays a critical role in the nigral iron deposits in PD. Nature Publishing Group UK 2022-04-30 /pmc/articles/PMC9056525/ /pubmed/35490179 http://dx.doi.org/10.1038/s41419-022-04704-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Jia, Fengju Li, Hongchang Jiao, Qian Li, Chaonan Fu, Lin Cui, Chunping Jiang, Hong Zhang, Lingqiang Deubiquitylase OTUD3 prevents Parkinson’s disease through stabilizing iron regulatory protein 2 |
title | Deubiquitylase OTUD3 prevents Parkinson’s disease through stabilizing iron regulatory protein 2 |
title_full | Deubiquitylase OTUD3 prevents Parkinson’s disease through stabilizing iron regulatory protein 2 |
title_fullStr | Deubiquitylase OTUD3 prevents Parkinson’s disease through stabilizing iron regulatory protein 2 |
title_full_unstemmed | Deubiquitylase OTUD3 prevents Parkinson’s disease through stabilizing iron regulatory protein 2 |
title_short | Deubiquitylase OTUD3 prevents Parkinson’s disease through stabilizing iron regulatory protein 2 |
title_sort | deubiquitylase otud3 prevents parkinson’s disease through stabilizing iron regulatory protein 2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9056525/ https://www.ncbi.nlm.nih.gov/pubmed/35490179 http://dx.doi.org/10.1038/s41419-022-04704-0 |
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