Shan X, Tashiro H, Lin CL.
The identification and characterization of oxidized RNAs in Alzheimer's disease.
J Neurosci. 2003 Jun 15;23(12):4913-21.
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This study by Shan et al. provides important new evidence for increased RNA oxidation and the biological consequence of the oxidized RNA in AD. Significantly increased levels of oxidized RNA nucleoside, 8-hydroxyguanosine (8OHG) were previously reported by in situ immunocytochemical analyses in vulnerable neurons of AD (Nunomura et al., 1999), Parkinson’s disease (Zhang et al., 1999), Down’s syndrome (Nunomura et al., 2000), and dementia with Lewy bodies (Nunomura et al., 2002), as well as in neurons of old rats in which memory loss was associated with the levels of RNA oxidation (Liu et al., 2002). Importantly, RNA oxidation in AD is an early-stage event in the pathological cascade (Nunomura et al., 2001).
Shan et al. used a biochemical approach, Northwestern blotting with a monoclonal anti-8OHG antibody, to isolate and identify oxidized RNA species and showed that significant amount of poly (A)+ mRNAs were oxidized in AD brains, which was further confirmed by cDNA synthesis and Southern blotting of the immunoprecipitated mRNAs. Interestingly, filter array analyses of the identified oxidized mRNAs revealed that some species were more susceptible to oxidative damage in AD. Some of the identified known oxidized transcripts are related to AD, which include p21ras, MAPK kinase 1, carbonyl reductase, SOD1, ApoD, calpains, etc., but not AƒÀPP or tau. Furthermore, the authors investigated the biological consequence of oxidatively damaged mRNAs by expressing them in cell lines and showed that (i) oxidized mRNAs were as stable as nonoxidized mRNAs, (ii) oxidized mRNAs lead to loss of normal protein level and protein function, and (iii) oxidized mRNAs might produce defective proteins leading to protein aggregation. These results strongly suggest significant roles of RNA oxidation in the pathogenesis of AD. However, this study focuses on mRNA species that account for only a few percent of total cellular RNA. The question whether the other RNA species and cytosolic free nucleotide pool are the primary targets for oxidation in AD still remains unanswered. In situ immunoelectronmicroscopy revealed that subcellular localization of 8OHG was associated with ribosomal structures in neurons of AD (Nunomura et al., 2001). Not only mRNAs but also ribosomal RNAs and/or transfer RNAs are potential targets for oxidative damage in AD.
One of the most striking findings of this study is that mRNAs are not randomly hit by free radicals in AD, while no common motifs or structures were found in the oxidatively susceptible mRNA species. Further investigation of the highly oxidized mRNAs that may be found not only in AD but also in Parkinson disease and dementia with Lewy bodies as well as aged animals possibly provides keys to understand the mechanisms of brain aging and age-associated neurodegenerative disorders.
Nunomura A, Chiba S, Kosaka K, Takeda A, Castellani RJ, Smith MA, Perry G.
Neuronal RNA oxidation is a prominent feature of dementia with Lewy bodies.
Neuroreport. 2002 Nov 15;13(16):2035-9.
Zhang J, Perry G, Smith MA, Robertson D, Olson SJ, Graham DG, Montine TJ.
Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons.
Am J Pathol. 1999 May;154(5):1423-9.
Nunomura A, Perry G, Pappolla MA, Friedland RP, Hirai K, Chiba S, Smith MA.
Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome.
J Neuropathol Exp Neurol. 2000 Nov;59(11):1011-7.
Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN.
Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid.
Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2356-61.
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA.
Oxidative damage is the earliest event in Alzheimer disease.
J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67.
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