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      Dopaminergic neurons show increased low-molecular-mass protein 7 activity induced by 6-hydroxydopamine in vitro and in vivo

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          Abstract

          Background

          Abnormal expression of major histocompatibility complex class I (MHC-I) is increased in dopaminergic (DA) neurons in the substantia nigra (SN) in Parkinson’s disease (PD). Low-molecular-mass protein 7 (β5i) is a proteolytic subunit of the immunoproteasome that regulates protein degradation and the MHC pathway in immune cells.

          Methods

          In this study, we investigated the role of β5i in DA neurons using a 6-hydroxydopamine (6-OHDA) model in vitro and vivo.

          Results

          We showed that 6-OHDA upregulated β5i expression in DA neurons in a concentration- and time-dependent manner. Inhibition and downregulation of β5i induced the expression of glucose-regulated protein (Bip) and exacerbated 6-OHDA neurotoxicity in DA neurons. The inhibition of β5i further promoted the activation of Caspase 3-related pathways induced by 6-OHDA . β5i also activated transporter associated with antigen processing 1 (TAP1) and promoted MHC-I expression on DA neurons.

          Conclusion

          Taken together, our data suggest that β5i is activated in DA neurons under 6-OHDA treatment and may play a neuroprotective role in PD.

          Electronic supplementary material

          The online version of this article (10.1186/s40035-018-0125-9) contains supplementary material, which is available to authorized users.

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          Most cited references49

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          Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress.

          Ulrike Seifert, Lukasz P Bialy, Frédéric Ebstein … (2010)
          Interferon (IFN)-induced immunoproteasomes (i-proteasomes) have been associated with improved processing of major histocompatibility complex (MHC) class I antigens. Here, we show that i-proteasomes function to protect cell viability under conditions of IFN-induced oxidative stress. IFNs trigger the production of reactive oxygen species, which induce protein oxidation and the formation of nascent, oxidant-damaged proteins. We find that the ubiquitylation machinery is concomitantly upregulated in response to IFNs, functioning to target defective ribosomal products (DRiPs) for degradation by i-proteasomes. i-proteasome-deficiency in cells and in murine inflammation models results in the formation of aggresome-like induced structures and increased sensitivity to apoptosis. Efficient clearance of these aggregates by the enhanced proteolytic activity of the i-proteasome is important for the preservation of cell viability upon IFN-induced oxidative stress. Our findings suggest that rather than having a specific role in the production of class I antigens, i-proteasomes increase the peptide supply for antigen presentation as part of a more general role in the maintenance of protein homeostasis. Copyright 2010 Elsevier Inc. All rights reserved.
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            The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg.

            Aaron Ciechanover, Patrik Brundin (2003)
            The ubiquitin-proteasome system targets numerous cellular proteins for degradation. In addition, modifications by ubiquitin-like proteins as well as proteins containing ubiquitin-interacting and -associated motifs modulate many others. This tightly controlled process involves multiple specific and general enzymes of the system as well as many modifying and ancillary proteins. Thus, it is not surprising that ubiquitin-mediated degradation/processing/modification regulates a broad array of basic cellular processes. Moreover, aberrations in the system have been implicated, either as a primary cause or secondary consequence, in the pathogenesis of both inherited and acquired neurodegenerative diseases. Recent findings indicate that the system is involved in the pathogenesis of Parkinson's, Alzheimer's, Huntington's, and Prion diseases as well as amyotrophic lateral sclerosis. This raises hopes for a better understanding of the pathogenetic mechanisms involved in these diseases and for the development of novel, mechanism-based therapeutic modalities.
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              A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis.

              Tony Muchamuel, Michael Basler, Monette Aujay … (2009)
              The immunoproteasome, a distinct class of proteasome found predominantly in monocytes and lymphocytes, is known to shape the antigenic repertoire presented on class I major histocompatibility complexes (MHC-I). However, a specific role for the immunoproteasome in regulating other facets of immune responses has not been established. We describe here the characterization of PR-957, a selective inhibitor of low-molecular mass polypeptide-7 (LMP7, encoded by Psmb8), the chymotrypsin-like subunit of the immunoproteasome. PR-957 blocked presentation of LMP7-specific, MHC-I-restricted antigens in vitro and in vivo. Selective inhibition of LMP7 by PR-957 blocked production of interleukin-23 (IL-23) by activated monocytes and interferon-gamma and IL-2 by T cells. In mouse models of rheumatoid arthritis, PR-957 treatment reversed signs of disease and resulted in reductions in cellular infiltration, cytokine production and autoantibody levels. These studies reveal a unique role for LMP7 in controlling pathogenic immune responses and provide a therapeutic rationale for targeting LMP7 in autoimmune disorders.
              Article 0 comments Cited 177 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jian-Xing He: drjianxing.he@gmail.com
                Ping-Yi Xu: pingyixu@sina.com
                Journal
                Journal ID (nlm-ta): Transl Neurodegener
                Journal ID (iso-abbrev): Transl Neurodegener
                Title: Translational Neurodegeneration
                Publisher: BioMed Central (London )
                ISSN (Electronic): 2047-9158
                Publication date (Electronic): 17 August 2018
                Publication date PMC-release: 17 August 2018
                Publication date Collection: 2018
                Volume: 7
                Electronic Location Identifier: 19
                Affiliations
                [1 ]GRID grid.470124.4, Department of Neurology, , First Affiliated Hospital of Guangzhou Medical University, ; Guangzhou, 510120 Guangdong China
                [2 ]GRID grid.452402.5, Department of Neurology, , Qilu Hospital of Shandong University, ; Jinan, 250012 Shandong China
                [3 ]GRID grid.412615.5, Department of Neurology, , First Affiliated Hospital of Sun Yat-sen University, ; Guangzhou, 510080 Guangdong China
                [4 ]ISNI 0000 0004 1799 3993, GRID grid.13394.3c, Department of Neurology, , Second Affiliated Hospital of Xinjiang Medical University, ; Urumchi, 830011 Xinjiang China
                [5 ]Clinic Brain Center, Guangzhou Hospital of Integrated Traditional and Western Medicine, Guangzhou, 510800 Guangdong China
                [6 ]ISNI 0000 0000 8877 7471, GRID grid.284723.8, Department of Blood Transfusion, , Fifth Affiliated Hospital Southern Medical University, ; Guangzhou, 510900 Guangdong China
                [7 ]GRID grid.470124.4, Department of Thoracic Surgery, , First Affiliated Hospital of Guangzhou Medical University, ; Guangzhou, 510120 Guangdong China
                Article
                Publisher ID: 125
                DOI: 10.1186/s40035-018-0125-9
                PMC ID: 6097308
                PubMed ID: 30128145
                SO-VID: 15d127de-e3e7-4bbb-bf58-10f030915d27
                Copyright © © The Author(s). 2018
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 23 January 2018
                Date accepted : 30 July 2018
                Funding
                Funded by: National Key R&D Program of China
                Award ID: 2016YFC1306600
                Award ID: SQ2017YFSF110116
                Funded by: National Natural Science Foundation of China
                Award ID: 81701254
                Award ID: 81471292
                Award ID: U1603281
                Award ID: U1503222
                Award ID: 81501100
                Award ID: 81430021
                Funded by: Science Foundation of Guangdong of China
                Award ID: 2015A030311021
                Funded by: a technology project of Guangzhou
                Award ID: 201504281820463
                Funded by: Shandong Provincial Natural Science Foundation
                Award ID: BS2015YY041
                Funded by: Science and Technology of Guangdong of China
                Award ID: 2013B022000026
                Funded by: Collaborative Innovation Foundation of Guangzhou Science and Technology Bureau
                Award ID: 2018-1202-SF-0019
                Funded by: International Project of Science and Technology for Guangdong
                Award ID: 2016A050502025
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                ScienceOpen disciplines: Neurosciences
                Keywords: parkinson’s disease,6-hydroxydopamine,immunoproteasome,tap1
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: parkinson’s disease, 6-hydroxydopamine, immunoproteasome, tap1

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