Abstract
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. 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. 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). 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.
Highlights
Machado–Joseph disease (MJD), referred to as spinocerebellar ataxia type 3 (SCA3/MJD), is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion (CAGexp) at ATXN3, the gene that codes for ataxin-3
Considering the hypothesis of an oxidative stress imbalance in SCA3/MJD that may precede disease onset, we aimed to evaluate the peripheral ROS production and antioxidant defense capacity in symptomatic and presymptomatic SCA3/ MJD individuals and a control population
The levels of the ROS marker DCFH-DA 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 Healthy Symptomatic Presymptomatic controls SCA3/MJD
Summary
Machado–Joseph disease (MJD), referred to as spinocerebellar ataxia type 3 (SCA3/MJD), is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion (CAGexp) at ATXN3, the gene that codes for ataxin-3. SCA3/ MJD is part of the so-called group of polyglutamine (PolyQ) disorders [1]; it is the most common form of SCA worldwide [2], with a minimal prevalence of 6:100,000 in Rio Grande do Sul, Brazil [3, 4]. Spinocerebellar ataxia type 3/Machado–Joseph disease onset typically occurs at approximately 32–40 years of age [2, 3, 5, 6]. Extrapyramidal, and peripheral nerve findings occur during the disease course [1]. The median survival time after onset is 21 years [7]
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