Circular RNAs — a modern perspective on the molecular mechanisms of neurologic diseases in humans and prospects for therapeutic agents

Abstract

In mammals, the brain exhibits significantly higher expression levels of various noncoding RNAs (ncRNAs) compared to other organs. Among these, circular RNAs (circRNAs) have recently emerged as a distinct class of ncRNAs. CircRNAs are formed by back-splicing and fusion of exons, introns, or both, resulting in covalently closed loops. Abundant in the brain, circRNAs levels increase during development and persist into adulthood. The functional significance and mechanisms of circRNA action are subjects of ongoing search, with indications that they regulate the transcription of host genes and sequestration of miRNAs and RNA binding proteins. Some circRNAs have also shown potential for translation, giving rise to peptides. In a healthy brain, circRNA expression and abundance are carefully regulated spatiotemporally. However, altered expression of circRNAs is associated with several disorders, including brain tumor growth and acute and chronic neurodegenerative disorders. This is believed to be through their impact on mechanisms such as angiogenesis, neuronal plasticity, autophagy, apoptosis, and inflammation. The unique properties of circRNAs make them promising molecular biomarkers, especially in the context of neurodegenerative diseases. This review provides a comprehensive overview of circRNAs, focusing on their role in the pathogenesis of major neurodegenerative disorders, namely, Alzheimers disease, frontotemporal dementia, Parkinsons disease, schizophrenia, and amyotrophic lateral sclerosis (ALS). Additionally, it discusses the potential utility of circRNAs in biomarker discovery for these debilitating conditions.