New Findings Implicate Circular RNA in the Development of Neurodegenerative Diseases

A recent paper described new findings that shed light on the production and function of circular RNA molecules (circRNA) in animal neuronal tissue.

CircRNA is a type of noncoding RNA that, unlike linear RNA, forms a covalently closed continuous loop. In circular RNA the 3' and 5' ends normally present in an RNA molecule have been joined together. This feature confers numerous properties to circular RNAs, many of which have only recently been identified. Though many of these circular RNAs arise from otherwise protein coding genes, circular RNAs produced in the cell have not been shown to code for proteins.

Investigators at The Hebrew University of Jerusalem (Israel) reported in the September 18, 2014, online edition of the journal Molecular Cell that animal circRNAs were generated co-transcriptionally and that their production rate was mainly determined by intronic sequences—filler DNA that separates coding regions on the chromosomes.

The investigators demonstrated that the process of circularization and that of normal splicing competed against each other, and that these mechanisms were tissue specific and conserved in animals. To further refine these findings, they concentrated on the gene for the protein muscleblind (muscleblind-like splicing regulator 1), which generates circularized RNA in flies and humans. They found that this circRNA (circMbl) and its flanking introns contained conserved muscleblind binding sites, which were strongly and specifically bound by muscleblind. Modulation of muscleblind levels strongly affected circMbl biosynthesis, and this effect was dependent on the muscleblind binding sites.

Since defects in muscleblind function have been linked to the severe degenerative disease myotonic dystrophy and since high levels of circRNAs are found in brain tissue, it may be that these molecules play a role in development of myotonic dystrophy and possibly other neurodegenerative diseases.

Senior author Dr. Sebastian Kadener, senior lecturer in biological chemistry at The Hebrew University of Jerusalem, said, "This research is significant from several perspectives. By mapping how circRNAs are produced, it helps advance our understanding of general molecular biology. In addition, it might be strongly relevant for understanding and eventually treating degenerative diseases both in muscle and the brain."

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