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Overproduction of free radicals can damage cellular components resulting in progressive physiological dysfunction, which has been implicated in many human diseases. Oxidative damage to RNA received little attention until the past decade. Recent studies indicate that RNA, such as messenger RNA and ribosomal RNA, is very vulnerable to oxidative damage. RNA oxidation is not a consequence of dying cells but an early event involved in pathogenesis. Oxidative modification to RNA results in disturbance of the translational process and impairment of protein synthesis, which can cause cell deterioration or even cell death. In this review, we discuss the mechanisms of oxidative damage to RNA and the possible biological consequences of damaged RNA. Furthermore, we review recent evidence suggesting that oxidative damage to RNA may contribute to progression of many human diseases.

In the past decade, RNA oxidation has caught the attention of many researchers, working to uncover its role in the pathogenesis of neurodegenerative diseases. It has been well documented that RNA oxidation is involved in a wide variety of neurological diseases and is an early event in the process of neurodegeneration. The analysis of oxidized RNA species revealed that at least messenger RNA (mRNA) and ribosomal RNA (rRNA) are damaged in several neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis (ALS). The magnitude of the RNA oxidation, at least in mRNA, is significantly high at the early stage of the disease. Oxidative damage to mRNA is not random but selective and many oxidized mRNAs are related to the pathogenesis of the disease. Several studies have suggested that oxidative modification of RNA affects the translational process and consequently produces less protein and/or defective protein. Furthermore, several proteins have been identified to be involved in handling of damaged RNA. Although a growing body of studies suggests that oxidative damage to RNA may be associated with neuron deterioration, further investigation and solid evidence are needed. In addition, further uncovering of the consequences and cellular handling of the oxidatively damaged RNA should be important focuses in this area and may provide significant insights into the pathogenesis of neurodegenerative diseases.

Cytoplasmic RNA oxidation is a prominent feature of vulnerable neurons in the brains of Alzheimer's disease (AD) patients. We previously demonstrated that messenger RNAs (mRNA) are oxidized in AD brains. However, the magnitude of the mRNA oxidation is unclear. In the present study, we separated oxidized mRNAs from non-oxidized mRNAs by immunoprecipitation and then quantitatively analyzed both mRNA fractions. Surprisingly, 30-70% of the mRNAs isolated from AD frontal cortices were oxidized while the abundance of oxidized mRNAs was low in age-matched normal controls. Furthermore, we previously showed that some mRNA species are more susceptible to oxidative damage. Here, we quantified the degree of oxidation for individual mRNA species that were previously found to be oxidized in AD. Quantitative analysis revealed that the relative amounts of oxidized transcripts reach 50-70% for some mRNA species. These high abundances implicate the potential contribution of mRNA oxidation to the pathogenesis of AD.

It has been shown that cytoplasmic RNA oxidation occurs to a great extent in the brains of Alzheimer's disease (AD) patients. The goal of this study was to isolate and identify oxidized RNA species in AD. We show that significant amounts of poly(A)+ mRNAs are oxidized in AD brains. RNA oxidation is not random but highly selective. Importantly, many identified oxidized mRNA species have been implicated in the pathogenesis of AD. Quantitative analysis revealed that some mRNA species are more susceptible to oxidative damage. We also investigated the biological consequence of oxidatively damaged mRNAs by expressing them in cell lines. Our data indicated that abnormal processing of proteins occurred to the oxidized mRNAs. This may implicate the potential contribution of RNA oxidation in the pathogenesis of AD.

BackgroundAccumulating evidence indicates that RNA oxidation is involved in a wide variety of neurological diseases and may be associated with neuronal deterioration during the process of neurodegeneration. However, previous studies were done in postmortem tissues or cultured neurons. Here, we used transgenic mice to demonstrate the role of RNA oxidation in the process of neurodegeneration.Methodology/principal findingsWe demonstrated that messenger RNA (mRNA) oxidation is a common feature in amyotrophic lateral sclerosis (ALS) patients as well as in many different transgenic mice expressing familial ALS-linked mutant copper-zinc superoxide dismutase (SOD1). In mutant SOD1 mice, increased mRNA oxidation primarily occurs in the motor neurons and oligodendrocytes of the spinal cord at an early, pre-symptomatic stage. Identification of oxidized mRNA species revealed that some species are more vulnerable to oxidative damage, and importantly, many oxidized mRNA species have been implicated in the pathogenesis of ALS. Oxidative modification of mRNA causes reduced protein expression. Reduced mRNA oxidation by vitamin E restores protein expression and partially protects motor neurons.Conclusion/significanceThese findings suggest that mRNA oxidation is an early event associated with motor neuron deterioration in ALS, and may be also a common early event preceding neuron degeneration in other neurological diseases.

Overproduction of free radicals can damage cellular components resulting in progressive physiological dysfunction, which has been implicated in many human diseases. Oxidative damage to RNA received little attention until the past decade. Recent studies indicate that RNA, such as messenger RNA and ribosomal RNA, is very vulnerable to oxidative damage. RNA oxidation is not a consequence of dying cells but an early event involved in pathogenesis. Oxidative modification to RNA results in disturbance of the translational process and impairment of protein synthesis, which can cause cell deterioration or even cell death. In this review, we discuss the mechanisms of oxidative damage to RNA and the possible biological consequences of damaged RNA. Furthermore, we review recent evidence suggesting that oxidative damage to RNA may contribute to progression of many human diseases. [ABSTRACT FROM AUTHOR]