Competing Endogenous RNA Regulations in Neurodegenerative Disorders: Current Challenges and Emerging Insights

The past decade has witnessed exciting breakthroughs that have contributed to the richness and complexity of a burgeoning modern RNA world, and one particular breakthrough—the competing endogenous RNA (ceRNA) hypothesis—has been described as the “Rosetta Stone” for decoding the RNA language used in regulating RNA crosstalk and modulating biological functions. The proposed far-reaching mechanism unites diverse RNA species and provides new insights into previously unrecognized RNA–RNA interactions and RNA regulatory networks that perhaps determine gene expression in an organized, hierarchical manner. The recently uncovered ceRNA regulatory loops and networks have emphasized the power of ceRNA regulation in a wide range of developmental stages and pathological contexts, such as in tumorigenesis and neurodegenerative disorders. Although the ceRNA hypothesis drastically enhanced our understanding of RNA biology, shortly after the hypothesis was proposed, disputes arose in relation mainly to minor discrepancies in the reported effects of ceRNA regulation under physiological conditions, and this resulted in ceRNA regulation becoming an extensively studied and fast-growing research field. Here, we focus on the evidence supporting ceRNA regulation in neurodegenerative disorders and address three critical points related to the ceRNA regulatory mechanism: the microRNA (miRNA) and ceRNA hierarchies in cross-regulations; the balance between destabilization and stable binding in ceRNA–miRNA interactions; and the true extent to which ceRNA regulatory mechanisms are involved in both health and disease, and the experimental shortcomings in current ceRNA studies.