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      Peripheral Oxidative Stress Biomarkers in Spinocerebellar Ataxia Type 3/Machado–Joseph Disease

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , * , 1 , 1 , 1 , 1 , 4 , 6 , 8 , 6 , 8 , 4 , 3 , 5 , 8 , 5 , 8 , 4 , 4 , 3 , 5 , 9 , 1 , 10 , 11 , 12 , 11 , 12 , 3 , 4 , 6 , 7 , 8 , 1 , 10
      Frontiers in Neurology
      Frontiers Media S.A.
      spinocerebellar ataxia type 3, Machado–Joseph disease, oxidative stress, reactive oxygen species, polyglutamine disorders

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          Abstract

          Objectives

          Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) is a polyglutamine disorder with no current disease-modifying treatment. Conformational changes in mutant ataxin-3 trigger different pathogenic cascades, including reactive oxygen species (ROS) generation; however, the clinical relevance of oxidative stress elements as peripheral biomarkers of SCA3/MJD remains unknown. We aimed to evaluate ROS production and antioxidant defense capacity in symptomatic and presymptomatic SCA3/MJD individuals and correlate these markers with clinical and molecular data with the goal of assessing their properties as disease biomarkers.

          Methods

          Molecularly confirmed SCA3/MJD carriers and controls were included in an exploratory case–control study. Serum ROS, measured by 2′,7′-dichlorofluorescein diacetate (DCFH-DA) as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) antioxidant enzyme activities, levels were assessed.

          Results

          Fifty-eight early/moderate stage symptomatic SCA3/MJD, 12 presymptomatic SCA3/MJD, and 47 control individuals were assessed. The DCFH-DA levels in the symptomatic group were 152.82 nmol/mg of protein [95% confidence interval (CI), 82.57–223.08, p < 0.001] higher than in the control and 243.80 nmol/mg of protein (95% CI, 130.64–356.96, p < 0.001) higher than in the presymptomatic group. The SOD activity in the symptomatic group was 3 U/mg of protein (95% CI, 0.015–6.00, p = 0.048) lower than in the presymptomatic group. The GSH-Px activity in the symptomatic group was 13.96 U/mg of protein (95% CI, 5.90–22.03, p < 0.001) lower than in the control group and 20.52 U/mg of protein (95% CI, 6.79–34.24, p < 0.001) lower than in the presymptomatic group and was inversely correlated with the neurological examination score for spinocerebellar ataxias ( R = −0.309, p = 0.049).

          Conclusion

          Early/moderate stage SCA3/MJD patients presented a decreased antioxidant capacity and increased ROS generation. GSH-Px activity was the most promising oxidative stress disease biomarker in SCA3/MJD. Further longitudinal studies are necessary to identify both the roles of redox parameters in SCA3/MJD pathophysiology and as surrogate outcomes for clinical trials.

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          Most cited references28

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          Glutathione peroxidase.

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            The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study.

            To obtain quantitative data on the progression of the most common spinocerebellar ataxias (SCAs) and identify factors that influence their progression, we initiated the EUROSCA natural history study, a multicentric longitudinal cohort study of 526 patients with SCA1, SCA2, SCA3, or SCA6. We report the results of the 1- and 2-year follow-up visits. As the primary outcome measure we used the Scale for the Assessment and Rating of Ataxia (SARA, 0-40), and as a secondary measure the Inventory of Non-Ataxia Symptoms (INAS, 0-16) count. The annual increase of the SARA score was greatest in SCA1 (2.18 ± 0.17, mean ± SE) followed by SCA3 (1.61 ± 0.12) and SCA2 (1.40 ± 0.11). SARA progression in SCA6 was slowest and nonlinear (first year: 0.35 ± 0.34, second year: 1.44 ± 0.34). Analysis of the INAS count yielded similar results. Larger expanded repeats and earlier age at onset were associated with faster SARA progression in SCA1 and SCA2. In SCA1, repeat length of the expanded allele had a similar effect on INAS progression. In SCA3, SARA progression was influenced by the disease duration at inclusion, and INAS progression was faster in females. Our study gives a comprehensive quantitative account of disease progression in SCA1, SCA2, SCA3, and SCA6 and identifies factors that specifically affect disease progression.
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              Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation.

              Ataxin-3 (AT3), the disease protein in spinocerebellar ataxia type 3 (SCA3), has been associated with the ubiquitin-proteasome system and transcriptional regulation. Here we report that normal AT3 binds to target DNA sequences in specific chromatin regions of the matrix metalloproteinase-2 (MMP-2) gene promoter and represses transcription by recruitment of the histone deacetylase 3 (HDAC3), the nuclear receptor corepressor (NCoR), and deacetylation of histones bound to the promoter. Both normal and expanded AT3 physiologically interacted with HDAC3 and NCoR in a SCA3 cell model and human pons tissue; however, normal AT3-containing protein complexes showed increased histone deacetylase activity, whereas expanded AT3-containing complexes had reduced deacetylase activity. Consistently, histone analyses revealed an increased acetylation of total histone H3 in expanded AT3-expressing cells and human SCA3 pons. Expanded AT3 lost the repressor function and displayed altered DNA/chromatin binding that was not associated with recruitment of HDAC3, NCoR, and deacetylation of the promoter, allowing aberrant MMP-2 transcription via the transcription factor GATA-2. For transcriptional repression normal AT3 cooperates with HDAC3 and requires its intact ubiquitin-interacting motifs (UIMs), whereas aberrant transcriptional activation by expanded AT3 is independent of the UIMs but requires the catalytic cysteine of the ubiquitin protease domain. These findings demonstrate that normal AT3 binds target promoter regions and represses transcription of a GATA-2-dependent target gene via formation of histone-deacetylating repressor complexes requiring its UIM-associated function. Expanded AT3 aberrantly activates transcription via its catalytic site and loses the ability to form deacetylating repressor complexes on target chromatin regions.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/150062
                URI : http://frontiersin.org/people/u/422116
                URI : http://frontiersin.org/people/u/229744
                URI : http://frontiersin.org/people/u/467725
                URI : http://frontiersin.org/people/u/240893
                URI : http://frontiersin.org/people/u/322020
                URI : http://frontiersin.org/people/u/226613
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                20 September 2017
                2017
                : 8
                : 485
                Affiliations
                [1] 1Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS) , Porto Alegre, Brazil
                [2] 2Programa de Pós-Graduação em Saúde e Comportamento, Centro de Ciências da Vida e da Saúde, Universidade Católica de Pelotas (UCPel) , Pelotas, Brazil
                [3] 3Programa de Pós-Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul (UFRGS) , Porto Alegre, Brazil
                [4] 4Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre (HCPA) , Porto Alegre, Brazil
                [5] 5Serviço de Neurologia, Hospital de Clínicas de Porto Alegre (HCPA) , Porto Alegre, Brazil
                [6] 6Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre (HCPA) , Porto Alegre, Brazil
                [7] 7Departamento de Medicina Interna, Universidade Federal do Rio Grande do Sul (UFRGS) , Porto Alegre, Brazil
                [8] 8Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul (UFRGS) , Porto Alegre, Brazil
                [9] 9Departamento de Neurologia, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) , Porto Alegre, Brazil
                [10] 10Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS) , Porto Alegre, Brazil
                [11] 11Programa de Pós-Graduação em Epidemiologia, Universidade Federal do Rio Grande do Sul (UFRGS) , Porto Alegre, Brazil
                [12] 12Departamento de Estatística, Universidade Federal do Rio Grande do Sul (UFRGS) , Porto Alegre, Brazil
                Author notes

                Edited by: Mark Mapstone, University of California, Irvine, United States

                Reviewed by: Pedro Ribeiro, Federal University of Rio de Janeiro, Brazil; Silmar Teixeira, Federal University of Piauí, Brazil; E. Lezi, Duke University, United States

                *Correspondence: Jonas Alex Morales Saute, jsaute@ 123456hcpa.edu.br

                These authors have contributed equally to this work.

                Specialty section: This article was submitted to Movement Disorders, a section of the journal Frontiers in Neurology

                Article
                10.3389/fneur.2017.00485
                5611390
                28979235
                878ec838-81e9-45f3-850c-6fc79e394386
                Copyright © 2017 de Assis, Saute, Longoni, Haas, Torrez, Brochier, Souza, Furtado, Gheno, Russo, Monte, Castilhos, Schumacher-Schuh, D’Avila, Donis, de Mello Rieder, Souza, Camey, Leotti, Jardim and Portela.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 March 2017
                : 31 August 2017
                Page count
                Figures: 2, Tables: 1, Equations: 1, References: 33, Pages: 8, Words: 4811
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul 10.13039/501100004263
                Award ID: 09/0078-5
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico 10.13039/501100003593
                Award ID: 478888/2010-4
                Categories
                Neuroscience
                Original Research

                Neurology
                spinocerebellar ataxia type 3,machado–joseph disease,oxidative stress,reactive oxygen species,polyglutamine disorders

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