A Comparative Analysis to Study Editing of Small Noncoding BC200- and Alu Transcripts in Brain of Prion-Inoculated Rhesus Monkeys ( M. Mulatta )
Small retroelements (short interspersed elements, abbreviated SINEs) are abundant in vertebrate genomes. Using RNA isolated from rhesus monkey cerebellum and buffy coat, reverse-transcription polymerase chain reaction (RT PCR) was applied to clone cDNA of BC200 and Alu RNAs. Transcripts containing Alu-SINE sequences may be subjected to extensive RNA editing by ADAR (adenosine deaminases that act on RNA) deamination. Abundance of Alu transcripts was determined with real-time RT PCR and was significantly higher than BC200 (brain cytoplasmic) in cerebellum. BC200 transcripts were absent from buffy coat cells. Availability of the rhesus genome sequence allowed the BC200 transcripts to be mapped to the specific locus on chromosome 13. Both the qualitative and quantitative characteristics of BC 200 expression argue for the BC 200 transcripts being generated by RNA polymerase III. In cerebellum, Alu transcripts often possessed base exchanges (A to G) consistent with ADAR editing and, somewhat unexpectedly, C to T exchanges consistent with APOBEC (apolipoprotein B editing complex) editing. In contrast, the BC200 transcripts, which as RNA POLIII transcripts play a role in dendritic RNA translation, appeared not to be deaminated, despite the presence of editing of Alu in the same tissue. To assess whether neuronal disease might influence editing of BC200 and Alu-SINE transcripts in cerebellum, RNA was isolated from two rhesus monkeys that were inoculated with prions from human variant Creutzfeldt-Jakob disease (vCJD). Regardless of prion-induced neurodegeneration, no BC200 RNA editing was observed, while Alu RNA continued to show both ADAR and APOBEC editing. Thus, BC200 RNAs do not appear to become accessible to editing enzymes despite infected neurons being subjected to severe stress, damage, and eventually cell death.
Available from: Minati Singh
- "Not surprisingly, deregulation of RNA editing results in dysregulation of the nervous system (Kwak and Kawahara, 2005; Valente and Nishikura, 2005). Abnormal RNA editing has been implicated in epilepsy, schizophrenia, depression, suicide, prion-induced neurodegeneration, autosomal dominant episodic ataxia type I, Prader Willi syndrome (PWS), ALS, AD, and HD (Niswender et al., 1999; Sodhi et al., 2001; Gurevich et al., 2002; Iwamoto and Kato, 2003; Englander et al., 2005; Iwamoto et al., 2005; Kwak and Kawahara, 2005; Valente and Nishikura, 2005; Kishore and Stamm, 2006; Doe et al., 2009; Morabito et al., 2010; Singh et al., 2011; Kiesel et al., 2012). "
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ABSTRACT: RNA editing is an alteration in the primary nucleotide sequences resulting from a chemical change in the base. RNA editing is observed in eukaryotic mRNA, transfer RNA, ribosomal RNA, and non-coding RNAs (ncRNA). The most common RNA editing in the mammalian central nervous system is a base modification, where the adenosine residue is base-modified to inosine (A to I). Studies from ADAR (adenosine deaminase that act on RNA) mutants in Caenorhabditis elegans, Drosophila, and mice clearly show that the RNA editing process is an absolute requirement for nervous system homeostasis and normal physiology of the animal. Understanding the mechanisms of editing and findings of edited substrates has provided a better knowledge of the phenotype due to defective and hyperactive RNA editing. A to I RNA editing is catalyzed by a family of enzymes knows as ADARs. ADARs modify duplex RNAs and editing of duplex RNAs formed by ncRNAs can impact RNA functions, leading to an altered regulatory gene network. Such altered functions by A to I editing is observed in mRNAs, microRNAs (miRNA) but other editing of small and long ncRNAs (lncRNAs) has yet to be identified. Thus, ncRNA and RNA editing may provide key links between neural development, nervous system function, and neurological diseases. This review includes a summary of seminal findings regarding the impact of ncRNAs on biological and pathological processes, which may be further modified by RNA editing. NcRNAs are non-translated RNAs classified by size and function. Known ncRNAs like miRNAs, smallRNAs (smRNAs), PIWI-interacting RNAs (piRNAs), and lncRNAs play important roles in splicing, DNA methylation, imprinting, and RNA interference. Of note, miRNAs are involved in development and function of the nervous system that is heavily dependent on both RNA editing and the intricate spatiotemporal expression of ncRNAs. This review focuses on the impact of dysregulated A to I editing and ncRNAs in neurodegeneration.
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