Peripheral Oxidative Stress Biomarkers in Spinocerebellar Ataxia Type 3/Machado–Joseph Disease
ObjectivesSpinocerebellar 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 clinica...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2017-09-01
|
| Series: | Frontiers in Neurology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fneur.2017.00485/full |
| _version_ | 1818683858485248000 |
|---|---|
| author | Adriano M. de Assis Adriano M. de Assis Jonas Alex Morales Saute Jonas Alex Morales Saute Jonas Alex Morales Saute Jonas Alex Morales Saute Jonas Alex Morales Saute Aline Longoni Clarissa Branco Haas Vitor Rocco Torrez Andressa Wigner Brochier Gabriele Nunes Souza Gabriel Vasata Furtado Gabriel Vasata Furtado Tailise Conte Gheno Tailise Conte Gheno Aline Russo Thais Lampert Monte Thais Lampert Monte Raphael Machado Castilhos Artur Schumacher-Schuh Artur Schumacher-Schuh Rui D’Avila Karina Carvalho Donis Carlos Roberto de Mello Rieder Carlos Roberto de Mello Rieder Carlos Roberto de Mello Rieder Diogo Onofre Souza Diogo Onofre Souza Suzi Camey Suzi Camey Vanessa Bielefeldt Leotti Vanessa Bielefeldt Leotti Laura Bannach Jardim Laura Bannach Jardim Laura Bannach Jardim Laura Bannach Jardim Laura Bannach Jardim Luis Valmor Portela Luis Valmor Portela |
| author_facet | Adriano M. de Assis Adriano M. de Assis Jonas Alex Morales Saute Jonas Alex Morales Saute Jonas Alex Morales Saute Jonas Alex Morales Saute Jonas Alex Morales Saute Aline Longoni Clarissa Branco Haas Vitor Rocco Torrez Andressa Wigner Brochier Gabriele Nunes Souza Gabriel Vasata Furtado Gabriel Vasata Furtado Tailise Conte Gheno Tailise Conte Gheno Aline Russo Thais Lampert Monte Thais Lampert Monte Raphael Machado Castilhos Artur Schumacher-Schuh Artur Schumacher-Schuh Rui D’Avila Karina Carvalho Donis Carlos Roberto de Mello Rieder Carlos Roberto de Mello Rieder Carlos Roberto de Mello Rieder Diogo Onofre Souza Diogo Onofre Souza Suzi Camey Suzi Camey Vanessa Bielefeldt Leotti Vanessa Bielefeldt Leotti Laura Bannach Jardim Laura Bannach Jardim Laura Bannach Jardim Laura Bannach Jardim Laura Bannach Jardim Luis Valmor Portela Luis Valmor Portela |
| author_sort | Adriano M. de Assis |
| collection | DOAJ |
| description | ObjectivesSpinocerebellar 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.MethodsMolecularly 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.ResultsFifty-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).ConclusionEarly/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. |
| first_indexed | 2024-12-17T10:41:25Z |
| format | Article |
| id | doaj.art-c712334b2db44d84bedcb8a04f079aeb |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-17T10:41:25Z |
| publishDate | 2017-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-c712334b2db44d84bedcb8a04f079aeb2022-12-21T21:52:15ZengFrontiers Media S.A.Frontiers in Neurology1664-22952017-09-01810.3389/fneur.2017.00485265918Peripheral Oxidative Stress Biomarkers in Spinocerebellar Ataxia Type 3/Machado–Joseph DiseaseAdriano M. de Assis0Adriano M. de Assis1Jonas Alex Morales Saute2Jonas Alex Morales Saute3Jonas Alex Morales Saute4Jonas Alex Morales Saute5Jonas Alex Morales Saute6Aline Longoni7Clarissa Branco Haas8Vitor Rocco Torrez9Andressa Wigner Brochier10Gabriele Nunes Souza11Gabriel Vasata Furtado12Gabriel Vasata Furtado13Tailise Conte Gheno14Tailise Conte Gheno15Aline Russo16Thais Lampert Monte17Thais Lampert Monte18Raphael Machado Castilhos19Artur Schumacher-Schuh20Artur Schumacher-Schuh21Rui D’Avila22Karina Carvalho Donis23Carlos Roberto de Mello Rieder24Carlos Roberto de Mello Rieder25Carlos Roberto de Mello Rieder26Diogo Onofre Souza27Diogo Onofre Souza28Suzi Camey29Suzi Camey30Vanessa Bielefeldt Leotti31Vanessa Bielefeldt Leotti32Laura Bannach Jardim33Laura Bannach Jardim34Laura Bannach Jardim35Laura Bannach Jardim36Laura Bannach Jardim37Luis Valmor Portela38Luis Valmor Portela39Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilPrograma de Pós-Graduação em Saúde e Comportamento, Centro de Ciências da Vida e da Saúde, Universidade Católica de Pelotas (UCPel), Pelotas, BrazilPrograma de Pós-Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilServiço de Genética Médica, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilServiço de Neurologia, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilLaboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilDepartamento de Medicina Interna, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilServiço de Genética Médica, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilLaboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilPrograma de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilLaboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilPrograma de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilServiço de Genética Médica, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilPrograma de Pós-Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilServiço de Neurologia, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilPrograma de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilServiço de Neurologia, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilPrograma de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilServiço de Genética Médica, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilServiço de Genética Médica, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilPrograma de Pós-Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilServiço de Neurologia, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilDepartamento de Neurologia, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, BrazilPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil0Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil1Programa de Pós-Graduação em Epidemiologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil2Departamento de Estatística, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil1Programa de Pós-Graduação em Epidemiologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil2Departamento de Estatística, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilPrograma de Pós-Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilServiço de Genética Médica, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilLaboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, BrazilDepartamento de Medicina Interna, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilPrograma de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil0Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, BrazilObjectivesSpinocerebellar 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.MethodsMolecularly 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.ResultsFifty-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).ConclusionEarly/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.http://journal.frontiersin.org/article/10.3389/fneur.2017.00485/fullspinocerebellar ataxia type 3Machado–Joseph diseaseoxidative stressreactive oxygen speciespolyglutamine disorders |
| spellingShingle | Adriano M. de Assis Adriano M. de Assis Jonas Alex Morales Saute Jonas Alex Morales Saute Jonas Alex Morales Saute Jonas Alex Morales Saute Jonas Alex Morales Saute Aline Longoni Clarissa Branco Haas Vitor Rocco Torrez Andressa Wigner Brochier Gabriele Nunes Souza Gabriel Vasata Furtado Gabriel Vasata Furtado Tailise Conte Gheno Tailise Conte Gheno Aline Russo Thais Lampert Monte Thais Lampert Monte Raphael Machado Castilhos Artur Schumacher-Schuh Artur Schumacher-Schuh Rui D’Avila Karina Carvalho Donis Carlos Roberto de Mello Rieder Carlos Roberto de Mello Rieder Carlos Roberto de Mello Rieder Diogo Onofre Souza Diogo Onofre Souza Suzi Camey Suzi Camey Vanessa Bielefeldt Leotti Vanessa Bielefeldt Leotti Laura Bannach Jardim Laura Bannach Jardim Laura Bannach Jardim Laura Bannach Jardim Laura Bannach Jardim Luis Valmor Portela Luis Valmor Portela Peripheral Oxidative Stress Biomarkers in Spinocerebellar Ataxia Type 3/Machado–Joseph Disease Frontiers in Neurology spinocerebellar ataxia type 3 Machado–Joseph disease oxidative stress reactive oxygen species polyglutamine disorders |
| title | Peripheral Oxidative Stress Biomarkers in Spinocerebellar Ataxia Type 3/Machado–Joseph Disease |
| title_full | Peripheral Oxidative Stress Biomarkers in Spinocerebellar Ataxia Type 3/Machado–Joseph Disease |
| title_fullStr | Peripheral Oxidative Stress Biomarkers in Spinocerebellar Ataxia Type 3/Machado–Joseph Disease |
| title_full_unstemmed | Peripheral Oxidative Stress Biomarkers in Spinocerebellar Ataxia Type 3/Machado–Joseph Disease |
| title_short | Peripheral Oxidative Stress Biomarkers in Spinocerebellar Ataxia Type 3/Machado–Joseph Disease |
| title_sort | peripheral oxidative stress biomarkers in spinocerebellar ataxia type 3 machado joseph disease |
| topic | spinocerebellar ataxia type 3 Machado–Joseph disease oxidative stress reactive oxygen species polyglutamine disorders |
| url | http://journal.frontiersin.org/article/10.3389/fneur.2017.00485/full |
| work_keys_str_mv | AT adrianomdeassis peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT adrianomdeassis peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT jonasalexmoralessaute peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT jonasalexmoralessaute peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT jonasalexmoralessaute peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT jonasalexmoralessaute peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT jonasalexmoralessaute peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT alinelongoni peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT clarissabrancohaas peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT vitorroccotorrez peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT andressawignerbrochier peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT gabrielenunessouza peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT gabrielvasatafurtado peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT gabrielvasatafurtado peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT tailisecontegheno peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT tailisecontegheno peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT alinerusso peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT thaislampertmonte peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT thaislampertmonte peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT raphaelmachadocastilhos peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT arturschumacherschuh peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT arturschumacherschuh peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT ruidavila peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT karinacarvalhodonis peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT carlosrobertodemellorieder peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT carlosrobertodemellorieder peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT carlosrobertodemellorieder peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT diogoonofresouza peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT diogoonofresouza peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT suzicamey peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT suzicamey peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT vanessabielefeldtleotti peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT vanessabielefeldtleotti peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT laurabannachjardim peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT laurabannachjardim peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT laurabannachjardim peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT laurabannachjardim peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT laurabannachjardim peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT luisvalmorportela peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease AT luisvalmorportela peripheraloxidativestressbiomarkersinspinocerebellarataxiatype3machadojosephdisease |