Messenger RNA oxidation is an early event preceding cell death and causes reduced protein expression.
We previously reported that up to 50% of messenger RNAs (mRNA) are oxidatively damaged in the affected area of Alzheimer's disease (AD) brains. The role of RNA oxidation in the cell death process is unknown. In the present study, we used cortical primary dissociated cultures to investigate the relationship between RNA oxidation and neuron degeneration induced by various insults, including hydrogen peroxide, glutamate, and amyloid beta peptide. These insults mediate the production of reactive oxygen species and thus induce oxidative stress. The results showed that RNA oxidation was an early event far preceding cell death, not merely a consequence of dying cells. RNA oxidation occurred primarily in a distinct group of neurons that died later. Identification of oxidized RNA species revealed that significant amounts of mRNAs were oxidized and that some mRNA species were more susceptible to oxidative damage, consistent with findings in the AD brain. The level of protein corresponding to the oxidized mRNA species was significantly decreased. Polyribosome analysis indicated that oxidized bases in mRNAs caused ribosome stalling on the transcripts, which led to a decrease of protein expression. These results suggest that RNA oxidation may be directly associated with neuronal deterioration, rather than harmless epiphenomena, during the process of neurodegeneration.
Shan
Xiu
X
Department of Neuroscience, The Ohio State University, 333 W. 10th Ave., Columbus, OH 43210, USA.
Chang
Yueming
Y
Lin
Chien-liang Glenn
CL
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D001923:Brain Chemistry / Q000502:physiology*; D016923:Cell Death; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D016166:Free Radical Scavengers / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047468:Immunoprecipitation; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014158:Transcription, Genetic
D016166:Free Radical Scavengers; D016877:Oxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1