Lipid Peroxidation and Neurodegenerative Disease

Lipid peroxidation is a complex process involving the interaction of oxygen-derived free radicals with polyunsaturated fatty acids, resulting in a variety of highly reactive electrophilic aldehydes. Since 1975, lipid peroxidation has been extensively studied in a variety of organisms. As neurodegenerative diseases became better understood, research establishing a link between this form of oxidative damage, neurodegeneration, and disease has provided a wealth of knowledge to the scientific community. With the advent of proteomics in 1995, the identification of biomarkers for neurodegenerative disorders became of paramount importance to better understand disease pathogenesis and develop potential therapeutic strategies. This review focuses on the relationship between lipid peroxidation and neurodegenerative diseases. It also demonstrates how findings in current research support the common themes of altered energy metabolism and mitochondrial dysfunction in neurodegenerative disorders

Role of ROS and RNS Sources in Physiological and Pathological Conditions

There is significant evidence that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. Mitochondria have been thought to both play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including stimulation of opening of permeability transition pores. Until recently, the functional significance of ROS sources different from mitochondria has received lesser attention. However, the most recent data, besides confirming the mitochondrial role in tissue oxidative stress and protection, show interplay between mitochondria and other ROS cellular sources, so that activation of one can lead to activation of other sources. Thus, it is currently accepted that in various conditions all cellular sources of ROS provide significant contribution to processes that oxidatively damage tissues and assure their survival, through mechanisms such as autophagy and apoptosis

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Several studies demonstrated that oxidative damage is a characteristic feature of many neurodegenerative diseases. The accumulation of oxidatively modified proteins may disrupt cellular functions by affecting protein expression, protein turnover, cell signaling, and induction of apoptosis and necrosis, suggesting that protein oxidation could have both physiological and pathological significance. For nearly two decades, our laboratory focused particular attention on studying oxidative damage of proteins and how their chemical modifications induced by reactive oxygen species/reactive nitrogen species correlate with pathology, biochemical alterations, and clinical presentations of Alzheimer\u27s disease. This comprehensive article outlines basic knowledge of oxidative modification of proteins and lipids, followed by the principles of redox proteomics analysis, which also involve recent advances of mass spectrometry technology, and its application to selected age-related neurodegenerative diseases. Redox proteomics results obtained in different diseases and animal models thereof may provide new insights into the main mechanisms involved in the pathogenesis and progression of oxidative-stress-related neurodegenerative disorders. Redox proteomics can be considered a multifaceted approach that has the potential to provide insights into the molecular mechanisms of a disease, to find disease markers, as well as to identify potential targets for drug therapy. Considering the importance of a better understanding of the cause/effect of protein dysfunction in the pathogenesis and progression of neurodegenerative disorders, this article provides an overview of the intrinsic power of the redox proteomics approach together with the most significant results obtained by our laboratory and others during almost 10 years of research on neurodegenerative disorders since we initiated the field of redox proteomics

Restoration of enzymatic activity of energy related proteins in traumatic brain injured rats following the administration of gamma-glutamylcysteine ethyl ester

The function of the brain is dependent upon sufficient supply of glucose for energy metabolism. The glycolytic pathway and Kreb’s cycle are important in producing ATP for the brain. Brain dysfunction resulting from an external force is known as traumatic brain injury (TBI). TBI is associated with oxidative damage through the production of reactive oxygen/nitrogen species. Reduced energy metabolism is a consequence of TBI. Antioxidants are substances responsible for the inhibition of oxidation. Gamma-glutamylcysteine ethyl ester (GCEE) is an ethyl ester moiety of gamma-glutamylcysteine that exhibits antioxidant activity by increasing glutathione production. Previous studies have demonstrated that the administration of GCEE following TBI has protective effects against protein nitration. This study investigates the enzymatic activity of malate dehydrogenase which has been identified as being nitrated in moderate TBI. To test the hypothesis that the administration of GCEE will normalize enzymatic activity post-TBI, adult male Wistar rats were divided equally into three groups: Sham, Saline, and GCEE treatment (150 mg/kg). Rats in all groups (except sham) were subjected to a craniotomy and a moderate TBI via cortical contusion. Post-TBI rats in the saline group received an administration of saline (150 mg/kg), and rats in the GCEE treatment group received an administration of GCEE (same dosage). Upon sacrifice, brains were harvested and enzymatic activity was indirectly measured spectrophotometrically. Preliminary data demonstrates that the administration of GCEE post-TBI robustly increases enzymatic activity bolstering the hypothesis. These results indicate potential therapeutic strategies to restore energy related enzymatic activity in the brain post-TBI

Interview with Dr. Tanea Reed [video]

Dr. Tanea Reed, Assistant Professor in EKU\u27s Chemistry Department, is a National Institute of Health award recipient and 2010 Esterbauer award winner. Her research is in traumatic brain injury

Lipid Peroxidation and Tyrosine Nitration in Traumatic Brain Injury: Insights into Secondary Injury from Redox Proteomics

Traumatic brain injury (TBI) is a spontaneous event in which sudden trauma and secondary injury cause brain damage. Symptoms of TBI can range from mild to severe depending on extent of injury. The outcome can span from complete patient recovery to permanent memory loss and neurological decline. Currently, there is no known cure for TBI; however, immediate medical attention after injury is most beneficial for patient recovery. It is a well-established concept that imbalances in the production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and native antioxidant mechicanisms have been shown to increase oxidative stress. Over the years, proteomics has been used to identify specific biomarkers in diseases such as cancers and neurological disorders such as Alzheimer disease and Parkinson disease. As TBI is a risk factor for a multitude of neurological diseases, biomarkers for this phenomenon are a likely field of study in order to confirm diagnosis. This review highlights the current proteomics studies that investigated excessively nitrated proteins and those altered by lipid peroxidation in TBI. This review also highlights possible diagnostic measures and provides insights for future treatment strategies

Redox Proteomics in Some Age-Related Neurodegenerative Disorders or Models Thereof

Neurodegenerative diseases cause memory loss and cognitive impairment. Results from basic and clinical scientific research suggest a complex network of mechanisms involved in the process of neurodegeneration. Progress in treatment of such disorders requires researchers to better understand the functions of proteins involved in neurodegenerative diseases, to characterize their role in pathogenic disease mechanisms, and to explore their roles in the diagnosis, treatment, and prevention of neurodegenerative diseases. A variety of conditions of neurodegenerative diseases often lead to post-translational modifications of proteins, including oxidation and nitration, which might be involved in the pathogenesis of neurodegenerative diseases. Redox proteomics, a subset of proteomics, has made possible the identification of specifically oxidized proteins in neurodegenerative disorders, providing insight into a multitude of pathways that govern behavior and cognition and the response of the nervous system to injury and disease. Proteomic analyses are particularly suitable to elucidate post-translational modifications, expression levels, and protein-protein interactions of thousands of proteins at a time. Complementing the valuable information generated through the integrative knowledge of protein expression and function should enable the development of more efficient diagnostic tools and therapeutic modalities. Here we review redox proteomic studies of some neurodegenerative diseases

Role of ROS and RNS Sources in Physiological and Pathological Conditions

There is significant evidence that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. Mitochondria have been thought to both play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including stimulation of opening of permeability transition pores. Until recently, the functional significance of ROS sources different from mitochondria has received lesser attention. However, the most recent data, besides confirming the mitochondrial role in tissue oxidative stress and protection, show interplay between mitochondria and other ROS cellular sources, so that activation of one can lead to activation of other sources. Thus, it is currently accepted that in various conditions all cellular sources of ROS provide significant contribution to processes that oxidatively damage tissues and assure their survival, through mechanisms such as autophagy and apoptosis