Written by Siddharth Nath Edited by Dr. Ray Truant

Oxidative stress is a hot topic in neurodegenerative disease research. New findings from Dr. Jonathan Magaña’s lab in Mexico show increases in measures of damage from oxygen compounds in SCA7 patients versus healthy individuals. This suggests that this type of chemical stress may be a critical step in triggering the death of brain cells in SCA7.

You’re stressed – whether you like it or not

You may not realize it, but all of the cells in your body are, at some point or another, undergoing stress. Now, this isn’t the same as what we normally take the word “stress” to mean. Your cells aren’t cramming for an exam, nor are they worried about an upcoming job interview. Instead, stress at the cellular level refers to the challenges cells face in the form of environmental extremes (like temperature changes), mechanical damage, exposure to toxins, and dysregulation of stress responses.

A particularly nasty type of stress that cells must contend with is oxidative stress. This results from an imbalance in the levels of reactive oxygen species (hence the term ‘oxidative’) within a cell and the cell’s ability to clear away these species. Reactive oxygen species form inside of cells as a byproduct of normal metabolism, and every cell has mechanisms to help with their clearance. These mechanisms, however, can become impaired. This could end up being disastrous because, when not removed properly, reactive oxygen species can wreak havoc in the cell: they have the ability to directly damage every cellular component, including proteins, lipids, and DNA.

Interestingly, oxidative stress increases naturally as we age and is a normal part of growing older. Oxidative stress is a topic of intense study and has been implicated in everything from cancer and bone disease to other neurodegenerative disorders (such as Alzheimer’s disease and Huntington’s disease). An inability to cope with or respond to increases in oxidative stress associated with aging may explain why many neurodegenerative disorders occur later in life, despite the fact that affected individuals express the disease gene from birth.

A role for oxidative stress in SCA7?

To understand whether oxidative stress may play a role in SCA7, researchers from Dr. Jonathan Magaña’s lab in Mexico took blood samples from patients with SCA7 and from healthy individuals with a similar age and sex distribution (known as a ‘control’ group). They then looked at the levels of various biomarkers (measures of biological processes) known to be associated with oxidative stress in both groups.

To determine whether there was more oxidative stress in the SCA7 patient group versus the control group, the researchers evaluated biomarkers in three separate categories: lipid damage, protein damage, and antioxidant defense. By measuring lipid damage and protein damage, the researchers would be able to get a snapshot of the consequences of any oxidative stress by looking directly at damage to cellular components. By measuring levels of antioxidant defense, the team would have the ability to determine whether the damage they saw was indeed due to oxidative stress, and also whether or not SCA7 patients are able to respond effectively to reactive oxygen stress.

Hurricane ROS takes its toll

When comparing the SCA7 blood to healthy blood, researchers found significantly higher levels of lipid hydroperoxide (LHP) and malondialdehyde (MDA), markers of oxidative damage to lipids. On the protein side, levels of advanced oxidation protein products (AOPPs) and protein carbonyl derivatives, which form when proteins undergo oxidation, were also elevated. Interestingly, levels of a specific byproduct of oxidative protein damage, called dityrosines, were lower in patient samples in comparison to healthy controls.

The team also found an abnormal increase in the antioxidant defense response in SCA7 samples. Enzymes associated with antioxidant defense, such as glutathione reductase (GR), glutathione peroxidase (GPx), and paraoxonase-1 (PON-1), were elevated in patient blood. In addition, the capacity of patient cells to reduce copper ions was increased. This measure, known as CUPRAC, is a readout of a cell’s antioxidant activity.

Importantly, the researchers then took this data and compared it to the severity of SCA7 disease, age of onset, and CAG tract length to determine whether oxidative stress correlates with a specific disease presentation. Using the common ataxia evaluation scales (INAS, SARA, and Klockgether), which assess how severely ataxia is impacting a patient’s functioning, the team found a positive correlation between CAG repeat length and poorer performance on the evaluations. Moreover, the team found increased levels of two oxidative stress biomarkers (MDA and carbonyl levels) in patients with higher CAG repeat numbers, suggesting that more severe disease may be correlated with increased levels of oxidative stress.

Taken as a whole, this suggests that there is increased reactive oxygen stress in SCA7. Why this happens is still unclear, but what this research tells us is that cells from SCA7 patients have more damage from oxidative stress, and that their stress response mechanisms are highly activated in comparison to healthy controls. Plus, this work shows that SCA7 patients with higher CAG repeat lengths (which correlates with earlier age of onset and more severe disease) have increased levels of reactive oxygen stress in comparison to SCA7 patients with shorter CAG repeat lengths.

 De-stressing for the road ahead

While this research offers valuable insight into what’s going on in the brains of SCA7 patients, it does not tell us how mutant ataxin-7 may contribute to an increase in oxidative stress. Also, it is still not clear whether the antioxidant stress response, albeit activated, is functioning properly in SCA7 patients.

Nonetheless, a link between oxidative stress and SCA7 is compelling, to say the least, and provides a springboard for future research. Determining how mutant ataxin-7 may contribute to oxidative damage will be a major subject of further studies, but in the meantime, we may be able to use some of the potential biomarkers identified in this study to track the progression of SCA7 in patients. This is important because current ataxia rating scales (such as the SARA) can have substantial variability between clinicians. A more quantitative measure, like blood levels of oxidative damage markers, could allow for more reliable tracking of disease.

Key Terms

Oxidative stress: A type of disturbance in the normal functioning of a cell caused by an imbalance in the levels of reactive oxygen species. These oxygen species are produced as a normal byproduct of cellular metabolism and are usually cleared by the cell without much trouble. When cells are unable to sufficiently clear reactive oxygen species, these molecules begin to accumulate and cause damage to components that form a cell’s critical structures, such as lipids, proteins, and DNA. As we age, our cells naturally become less efficient at clearing reactive oxygen species and the level of oxidative stress we experience increases.

Biomarker: An objective, measurable indicator of a biological process. A biomarker allows clinicians and scientists to follow biology without doing any invasive tests or performing surgery. For example, low-density lipoprotein (LDL) or ‘bad cholesterol’ is a biomarker for heart disease. Your doctor can evaluate your risk for heart disease and track whether you condition is worsening or improving by checking the levels of LDL in your blood.

Ataxia scales: Scales used by clinicians and researchers to track ataxia disease progression in patients. By assigning scores to many different signs and symptoms, a patient’s disease stage and severity can be determined. The different scales have varied components and evaluate separate symptoms and clinical presentations. For more information, visit the Ataxia Study Group. These include INAS, SARA, and Klockgether.

Conflict of Interest Statement

The writer and editor have no conflicts to declare.

Citation of Article Reviewed

Torres-Ramos Y, Montoya-Estrada A, Cisneros B, et al. Oxidative stress in Spinocerebellar Ataxia Type 7 Is Associated with Disease Severity.Cerebellum, 2018. [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/29876803)