Abstract
Compared to sites in protein-coding sequences many more targets undergoing adenosine to inosine (A-to-I) RNA editing were discovered in non-coding regions of human cerebral transcripts, particularly in genetic transposable elements called retrotransposons. We review here the interaction mechanisms of RNA editing and retrotransposons and their impact on normal function and human neurological diseases. Exemplarily, A-to-I editing of retrotransposons embedded in protein-coding mRNAs can contribute to protein abundance and function via circular RNA formation, alternative splicing, and exonization or silencing of retrotransposons. Interactions leading to disease are not very well understood. We describe human diseases with involvement of the central nervous system including inborn errors of metabolism, neurodevelopmental disorders, neuroinflammatory and neurodegenerative and paroxysmal diseases, in which retrotransposons (Alu and/or L1 elements) appear to be causally involved in genetic rearrangements. Sole binding of single-stranded retrotransposon transcripts by RNA editing enzymes rather than enzymatic deamination may have a homeostatic effect on retrotransposon turnover. We also review evidence in support of the emerging pathophysiological function of A-to-I editing of retrotransposons in inflammation and its implication for different neurological diseases including amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's and Parkinson's disease, and epilepsy.
Highlights
The complexity of humans must be due to more than the number of their genes, because a dichotomy exists between the functional complexity of some organs, such as the brain, and the number of genes in humans compared to other organisms
In most if not all neurological diseases cited in this review (Table 1, Supplementary Text, Supplementary Table 1), transposable element (TE) were involved in genetic rearrangement and the association between rearrangement and disease cause was frequently convincing
The few RNA editing events at protein recoding sites appeared seemingly detached from previous reports about the overwhelming majority of edits in non-coding Alu sequences, and from the genetic rearrangements in the diseases discussed here
Summary
The complexity of humans must be due to more than the number of their genes, because a dichotomy exists between the functional complexity of some organs, such as the brain, and the number of genes in humans compared to other organisms. Alu exonization into the 3′ UTR was described to occur by RNA editing-mediated generation of a splice donor site in transcripts from the GPR81 gene, a G protein-coupled receptor with some expression in the brain (Athanasiadis et al, 2004). A FTD patient with a primary progressive aphasia phenotype was identified, who carried a compound heterozygous genetic rearrangement consisting of a non-sense mutation in the TBK1 gene and a deletion spanning OPTN exons 13–15.
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