Redox Proteomics: The Search for Cause and/or Effect in Disease

Redox proteomics aims at identifying and quantifying redox-based changes within the proteome both in normal cell signaling and under oxidative stress conditions. Proteins are common targets for oxygen reactions, and researchers have described many posttranslational modifications leading to changes in the structure and/or function of oxidized proteins.¹ As part of their normal function, proteins regularly undergo reversible redox reactions. Under oxidative stress, however, they can be irreversibly damaged, potentially contributing to disease. Many studies provide evidence that alterations in redox homeostasis — and resulting damage mainly to proteins and lipids — are linked to several complex diseases, including type 2 diabetes, atherosclerosis, stroke, many types of cancer, Alzheimer’s disease, and Parkinson’s disease.² Numerous studies have examined potential biomarkers related to oxidative stress that may be predictive for different diseases. As well, drug manufacturers market vitamins A, E, and C as ‘antioxidants’ that may reduce the free radicals produced through oxidative stress.³

While the correlation between protein oxidation and human disease is widely recognized, ascertaining whether oxidation is a result of other underlying pathologies or a primary cause remains a challenge. In Alzheimer’s disease, for example, oxidative stress markers have been documented in proteins, DNA, and RNA. Protein oxidation is evidenced in Alzheimer’s patients’ brains by an increased presence of carbonylated, protein-bound HNE and 3-NT-modified proteins. One research team using a redox proteomics approach identified carbonylation in 12 distinct proteins involved in energy metabolism, pH regulation, amyloid beta peptide production, tau hyperphosphorylation, and mitochondrial function.⁴ Significantly, amyloid beta is the main component of the characteristic plaque deposits found in Alzheimer’s disease. Similarly, tau protein hyperphosphorylation can result in the tangled filaments also present in Alzheimer’s disease.

The question remains: Is the increase in protein carbonyls causal, or a sequel to disease onset? This question stands for all diseases linked to oxidative stress. The problem has been stalled by a lack of methods able to assess oxidative stress status and resulting damage in vivo in both humans and animal models. In the last few years, however, combined proteomics, mass spectrometry (MS), and more precise molecular technologies have contributed to a better understanding of oxidative modifications to proteins and their altered function.⁴ As we learn more about redox proteomics, we will be better able to sort out whether or not oxidation is a result or cause of disease.

References

1. Butterfield, D.A. and Dalle-Donne, I. (2012) ‘Redox Proteomics‘, Antioxidants & Redox Signaling, published online July 9, 2012. doi: 10.1089/ars.2012.4742

2. Dalle-Donne, I., et al. (2005) ‘Proteins as Biomarkers of Oxidative/Nitrosative Stress in Diseases: The Contribution of Redox Proteomics‘, Mass Spectrometry Reviews, 24 (1), (pp. 55-99)

3. Zaidi, S.M. and Banu, N. (2004) ‘Antioxidant potential of vitamins A, E and C in modulating oxidative stress in rat brain‘, Clinica Chimica Acta, 340 (1-2), (pp. 229-233)

4. Butterfield, D.A., et al. (2012) ‘Redox proteomics in selected neurodegenerative disorders: From its infancy to future applications’, Antioxidants & Redox Signaling, 17 (11), published online January 18, 2012. doi: 10.1089/ars.2011.4109