Circular RNA in human brain: Systematic review of synaptic functions and disease associations

Circular RNAs (circRNAs) are covalently closed, non-canonical transcripts, highly enriched in the mammalian brain and especially synaptic compartments. Generated via back-splicing of precursor mRNAs, their intrinsic stability and spatiotemporally regulated expression enable the modulating function for synaptic physiology through multiple mechanisms, including microRNA sequestration, RNA-binding protein (RBP) interaction, and cap-independent translation. Mounting evidence links dysregulation of brain-enriched circRNAs to the pathogenesis of diverse neurologic disorders, ranging from neurodegenerative conditions (Alzheimer's disease, Parkinson's disease) to neuropsychiatric and epileptic disorders. Beyond pathogenesis, circRNAs also hold biomedical potential, serving as biofluid biomarkers and therapeutic candidates as engineered aptamers. This review synthesizes current knowledge of circRNA biology in regulating brain synaptic function and contributing to neurologic disorders, also highlights unmet needs and key directions for advancing translational research. We introduce an online knowledge base: circrna.database4brain.com to centralize relevant resources.