RNA Editing—Systemic Relevance and Clue to Disease Mechanisms?

Figures

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  Figure 1. Principles of A-to-I RNA editing. The hand-drawing top left provides a schematic illustration of the deamination of adenosine to inosine (A-to-I). In contrast to APOBEC-dependent C-to-U RNA editing, ADARs do not need auxiliary proteins for deamination but rely on secondary mRNA structure motifs within introns (bottom-left). A-to-I RNA editing can lead to indicated (right-hand) amino acid recoding events. Selected edited products and their possible involvement in disease are discussed in this review article.

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  Figure 2. Pathophysiological implications of altered ADAR-dependent RNA editing in disease. Both up- and down-regulation of A-to-I RNA editing (indicated by orange and blue colors, respectively) were associated with several, different diseases. Note that up-regulation of GABAAR α3 RNA editing makes an exception as it plays a role in development (indicated by gray text color).

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  Figure 3. Principles of C-to-U RNA editing. The hand-drawing top left provides a schematic illustration of the deamination of cytidine to uridine (C-to-U). In contrast to ADAR-dependent A-to-I RNA editing, APOBEC needs auxiliary proteins for deamination as detailed in Table 1 and exemplified in the bottom-left panel. Thus, the mature mRNA can be RNA-edited. C-to-U RNA editing can lead to indicated (right-hand) amino acid recoding events. Some selected gene products associated with disease (in brackets) and their possible involvement in disease are discussed in this review article.

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  Figure 4. Pathophysiological implications of altered APOBEC-dependent RNA editing in disease. Both up- and down-regulation of C-to-U RNA editing (indicated by orange and blue colors, respectively) were associated with several, different diseases. However, compared to diseases that have been associated with altered A-to-I RNA editing, this list is rather short. In particular, in half of the cases, the question marks indicate global changes in C-to-U RNA editing due to changes in enzyme expression without identification of specific gene products that were associated with up- or down-regulation of the APOBEC enzymes in animal models or tissue samples of patients. The red framed example is discussed in more detail in this review article.

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  Figure 5. Example of a RNA editing-dependent bedside-to-bench approach. (A) GlyR C-to-U RNA editing leads to amino acid recoding in the ligand binding domain (P185L or P192L, indicated by the orange filled red framed arrow); modified from Legendre et al. (2009). (B) The amino acid recoding increases apparent GlyR affinity to glycine irrespectively of the subunit composition as discussed in the main text. Panel (B) is reproduced from Legendre et al. (2009) and shown here again for the purpose of clarity. (C) Increased RNA editing of GlyR-coding mRNA in patients with temporal lobe epilepsy (TLE) as documented in 2008 by Eichler and colleagues. In a corresponding mouse model of TLE RNA-edited GlyRs elicited different neuropsychiatric symptoms depending on the neuron type that expressed these receptor variants, compared to control animals without expression of RNA-edited GlyR and indicated by red framed yellow arrows and the black framed gray arrow, respectively, placed between (B,C). (D) It is the presynaptic function of RNA-edited GlyRs that is responsible for increased neuronal impact on network function and the neuron type-specific neuropsychiatric symptoms described in the main text and…