The Role of ELAV Protein in Shaping the Brain's Circular RNA Landscape

Recent research from the Max Planck Institute of Immunobiology and Epigenetics has uncovered a key mechanism responsible for the abundance of circular RNAs (circRNAs) in the nervous system. Circular RNAs are unique molecules that form closed loops instead of linear strands, conferring them with remarkable stability. These molecules are highly prevalent in neurons and are believed to play important roles in brain development, cognition, and neurodegenerative processes.

The study, published in Genes & Development, highlights the central role of the RNA-binding protein ELAV in regulating circRNA formation. The researchers found that ELAV acts as a master switch, promoting the production of circRNAs in developing neurons. When ELAV was removed from fruit fly embryos, neuronal circRNA levels dropped significantly—by over 75%. Conversely, introducing ELAV into cells with low circRNA levels triggered their formation. This evidence confirms ELAV’s pivotal role in circRNA regulation.

Mechanistically, ELAV binds to specific regions of precursor RNA, known as reverse complementary sequences (RCMs), located in the introns flanking the backsplice junction (BSJ). This binding facilitates the formation of secondary RNA structures that bring the splice sites into close proximity, favoring back-splicing and the creation of circRNAs. Furthermore, ELAV binding suppresses traditional linear splicing at these loci, channeling the process toward circularization.

The stability of circRNAs, due to their closed-loop structure, enables them to perform sustained regulatory tasks within neurons. They can influence gene activity, act as molecules that sequester other regulatory entities, or even encode proteins. The discovery of ELAV’s role in circRNA formation suggests that these molecules are purposefully generated and integral to brain function.

Considering the conservation of ELAV-like proteins across species—from flies to humans—these findings imply that similar mechanisms operate in the human brain. Manipulating ELAV or its equivalents could offer new avenues for understanding and potentially treating neurodegenerative diseases and other neurological conditions by modulating circRNA levels.