RNA editing as a therapeutic target for CNS disorders

The conversion of adenosine to inosine (A-to-I) by RNA editing is a widespread RNA processing event by which genomically encoded sequences are altered through site-specific deamination of adenosine residue(s) by a family of enzymes referred to as adenosine deaminases that act on RNA (ADARs). Notable targets of RNA editing in the CNS include transcripts encoding subunits of the AMPA and kainate (KA) subtypes of glutamate receptor, the α3 subunit of the GABA_A receptor, the serotonin 2C (5 HT_2C) receptor, and the K_v1.1 voltage-gated potassium channel. RNA editing can modulate the functional properties of the encoded protein products and variations in the editing of glutamate receptor subunit and 5 HT_2C mRNAs have been observed in several CNS disorders (Rula and Emeson, 2007), suggesting that modulation of RNA editing in the nervous system could represent a therapeutic strategy for the treatment of nervous system dysfunction.

A failure to edit GluR2 transcripts results in Ca²⁺-permeable AMPA receptors that can lead to excitotoxicity. Recent studies have observed a significant reduction in Q/R site editing for affected motor neurons isolated from patients with amyotrophic lateral sclerosis, suggesting that glutamatergic excitotoxicity may underlie the selective neuronal death of these motor neurons (Kwak and Kawahara, 2005). RNA editing of another site within GluR2 transcripts (R/G site) alters both the recovery rate and desensitization kinetics of AMPA receptors containing edited subunits (Rula and Emeson, 2007) and increased editing has been observed in the hippocampus of patients with temporal lobe epilepsies (Vollmar et al, 2004). Significant alterations in KA receptor editing and ADAR2 protein expression also have been seen following seizures in humans and rats, and genetically modified animals solely expressing a nonedited GluR6(Q) subunit demonstrate increased susceptibility to KA-induced seizures (Vissel et al, 2001), suggesting KA receptor editing may modulate seizure vulnerability.

Editing of 5 HT_2C receptor transcripts can generate up to 24 receptor isoforms that not only have distinct functional properties affecting constitutive activity and receptor/G-protein coupling, but also differ in their pattern of CNS expression (Rula and Emeson, 2007). Altered editing patterns have been observed in suicide victims with a history of major depression and in response to antidepressant treatment (Niswender et al, 2001; Gurevich et al, 2002), suggesting that editing may be involved in affective disorders and the maintenance of appropriate serotonergic neurotransmission.

Although no conclusive data have demonstrated that changes in RNA editing are causal for human brain disorders, the role of ADARs in the function of numerous receptors/channels highlights the potential for ADAR activity as a future target for the treatment of CNS dysfunction. Therapeutic modulation of A-to-I editing patterns for specific substrates is complicated by the fact that only two ADAR proteins have been shown to catalyze all known editing events in mammals, predicting that broad alterations in ADAR activity could result in untoward effects. Observations that RNA editing changes in CNS disorders may occur in specific brain regions, or even subpopulations of neurons, suggest that substrate- or region-selective approaches to modify editing represent more promising areas of research for the treatment of CNS disorders.