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      Neuroprotective Effect of E3 Ubiquitin Ligase RNF8 Against Ischemic Stroke via HDAC2 Stability Reduction and Reelin-Dependent GSK3β Inhibition

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          Abstract

          Loss of E3 ubiquitin ligase RING finger protein 8 (RNF8) may lead to neuronal DNA damage and apoptosis. In order to expand on our knowledge on the mechanistic basis underlying neuronal death in ischemic stroke, the present study sought to investigate the potential role of E3 ubiquitin ligase RNF8 on ischemic stroke and explore the underlying downstream mechanism. Middle cerebral artery occlusion (MCAO) in mice and oxygen–glucose deprivation/reoxygenation (OGD/R) in neurons were induced to simulate an ischemic stroke environment. It was found that downregulation of RNF8 and Reelin occurred in MCAO mice and OGD/R-exposed neurons. Silencing of RNF8 enhanced the MCAO-induced neuronal apoptosis and oxidative stress. Mechanistically, RNF8 enhanced the ubiquitination and degradation of HDAC2, thus attenuating OGD/R-induced neuronal apoptosis and oxidative stress. Moreover, HDAC2 inhibited Reelin expression through deacetylation of H3K27me3 in its promoter, causing reduced glycogen synthase kinase-3beta (GSK3β)-Ser9 phosphorylation and the resultant elevated GSK3β activity. By this mechanism, RNF8 alleviated ischemic stroke. Coherently, this study suggests that RNF8 plays a neuroprotective effect against ischemic stroke by downregulating HDAC2 expression and inducing Reelin-induced GSK3β inhibition.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s12035-022-02880-w.

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          Erasers of histone acetylation: the histone deacetylase enzymes.

          Edward Seto, Minoru Yoshida (2014)
          Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. In humans, there are 18 HDAC enzymes that use either zinc- or NAD(+)-dependent mechanisms to deacetylate acetyl lysine substrates. Although removal of histone acetyl epigenetic modification by HDACs regulates chromatin structure and transcription, deacetylation of nonhistones controls diverse cellular processes. HDAC inhibitors are already known potential anticancer agents and show promise for the treatment of many diseases.
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            SARS2-CoV-2 and Stroke in a New York Healthcare System

            Shadi Yaghi, Koto Ishida, José Salavert Torres … (2020)
            Background and Purpose: With the spread of coronavirus disease 2019 (COVID-19) during the current worldwide pandemic, there is mounting evidence that patients affected by the illness may develop clinically significant coagulopathy with thromboembolic complications including ischemic stroke. However, there is limited data on the clinical characteristics, stroke mechanism, and outcomes of patients who have a stroke and COVID-19. Methods: We conducted a retrospective cohort study of consecutive patients with ischemic stroke who were hospitalized between March 15, 2020, and April 19, 2020, within a major health system in New York, the current global epicenter of the pandemic. We compared the clinical characteristics of stroke patients with a concurrent diagnosis of COVID-19 to stroke patients without COVID-19 (contemporary controls). In addition, we compared patients to a historical cohort of patients with ischemic stroke discharged from our hospital system between March 15, 2019, and April 15, 2019 (historical controls). Results: During the study period in 2020, out of 3556 hospitalized patients with diagnosis of COVID-19 infection, 32 patients (0.9%) had imaging proven ischemic stroke. Cryptogenic stroke was more common in patients with COVID-19 (65.6%) as compared to contemporary controls (30.4%, P=0.003) and historical controls (25.0%, P<0.001). When compared with contemporary controls, COVID-19 positive patients had higher admission National Institutes of Health Stroke Scale score and higher peak D-dimer levels. When compared with historical controls, COVID-19 positive patients were more likely to be younger men with elevated troponin, higher admission National Institutes of Health Stroke Scale score, and higher erythrocyte sedimentation rate. Patients with COVID-19 and stroke had significantly higher mortality than historical and contemporary controls. Conclusions: We observed a low rate of imaging-confirmed ischemic stroke in hospitalized patients with COVID-19. Most strokes were cryptogenic, possibly related to an acquired hypercoagulability, and mortality was increased. Studies are needed to determine the utility of therapeutic anticoagulation for stroke and other thrombotic event prevention in patients with COVID-19.
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              Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders.

              Laura J. Falkenberg, Ricky W Johnstone, Helle Falkenberg (2014)
              Epigenetic aberrations, which are recognized as key drivers of several human diseases, are often caused by genetic defects that result in functional deregulation of epigenetic proteins, their altered expression and/or their atypical recruitment to certain gene promoters. Importantly, epigenetic changes are reversible, and epigenetic enzymes and regulatory proteins can be targeted using small molecules. This Review discusses the role of altered expression and/or function of one class of epigenetic regulators--histone deacetylases (HDACs)--and their role in cancer, neurological diseases and immune disorders. We highlight the development of small-molecule HDAC inhibitors and their use in the laboratory, in preclinical models and in the clinic.
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                Author and article information

                Contributors
                Zhi Huang:
                ORCID: http://orcid.org/0000-0001-9980-986X
                gydoctor@gmc.edu.cn
                Wenfeng Yu: 2291860147@qq.com
                Journal
                Journal ID (nlm-ta): Mol Neurobiol
                Journal ID (iso-abbrev): Mol Neurobiol
                Title: Molecular Neurobiology
                Publisher: Springer US (New York )
                ISSN (Print): 0893-7648
                ISSN (Electronic): 1559-1182
                Publication date (Electronic): 27 May 2022
                Pages: 1-15
                Affiliations
                [1 ]GRID grid.413458.f, ISNI 0000 0000 9330 9891, School of Basic Medical Science, , Guizhou Medical University, ; No. 9, Beijin Road, Guiyang, 550002 Guizhou Province People’s Republic of China
                [2 ]GRID grid.413458.f, ISNI 0000 0000 9330 9891, Department of Interventional Radiology, , The Affiliated Cancer Hospital of Guizhou Medical University, ; Guiyang, 550002 People’s Republic of China
                [3 ]GRID grid.413458.f, ISNI 0000 0000 9330 9891, School of Clinical Medicine, , Guizhou Medical University, ; Guiyang, 550002 People’s Republic of China
                [4 ]GRID grid.452244.1, Department of Interventional Radiology, , The Affiliated Hospital of Guizhou Medical University, ; No. 28, Guiyi Street, Guiyang, 550002 Guizhou Province People’s Republic of China
                Author information
                http://orcid.org/0000-0001-9980-986X
                Article
                Publisher ID: 2880
                DOI: 10.1007/s12035-022-02880-w
                PMC ID: 9135995
                PubMed ID: 35622272
                SO-VID: 8a6b0851-b0eb-4d54-b534-2e802b538123
                Copyright © © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
                License:

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                Date received : 28 June 2021
                Date accepted : 12 May 2022
                Funding
                Funded by: National Natural Science Foundation
                Award ID: 81860321
                Funded by: Science and Technology Planning Project of Baiyun District, Guiyang City, Baike Contract
                Award ID: (2019) No. 36
                Funded by: Regional Common Diseases and Adult Stem Cell Transformation Research Innovation Platform, Science and Technology Department of Guizhou Province
                Award ID: Guizhou Specific Grant (2019) 4008
                Funded by: The National Natural Science Foundation of China
                Award ID: 82060232
                Funded by: Science and Technology Plan Project of Guizhou Province, Science and Technology Department of Guizhou Province
                Award ID: Basic Science
                Award ID: Technology Cooperation [(2020) 1Z060]
                Funded by: Guizhou Science Foundation
                Award ID: (2017) 1149
                Categories
                Subject: Article

                ScienceOpen disciplines: Neurosciences
                Keywords: ischemic stroke,rnf8,hdac2,reelin,gsk3β,neuronal apoptosis,oxidative stress
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: ischemic stroke, rnf8, hdac2, reelin, gsk3β, neuronal apoptosis, oxidative stress

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