February 8, 2023 — The Hebrew University of Jerusalem (HU) and University of Kentucky researchers are exploring whether a new type of protein substantially increases the molecular complexity in the brain and improves its function. This may have implications for the study of neurological diseases such as schizophrenia, epilepsy, and autism.

The researchers recently received a $1 million joint grant from the American National Science Foundation (NSF) and the United States-Israel Binational Science Foundation (BSF) to study new aspects of RNA biology.

The team of researchers, led by Prof. Ruth Sperling of the Hebrew University Alexander Silberman Institute of Life Sciences, together with Prof. Stephen Stamm from the School of Medicine in Lexington, Kentucky, hypothesize that a new type of primate-specific proteins, translated from molecules of circular RNA, improves the brain’s function in relation to other organisms with a similar number of genes.

RNA is the mediator in turning instructions encoded in DNA into cellular proteins. As part of the process, the RNA is heavily modified: some pieces are cut out and the remaining parts are put back together, to assemble a new line of RNA – which fundamentally changes their composition. Sometimes, these parts form in circles, creating circular RNA.

Circular RNAs are mostly found in the brain and their formation is promoted by genomic elements specific to humans and other primates, called Alu-elements. The human genome consists of about 11% Alu-elements and their expansion in primates correlates with brain complexity.

“For the first time, the team of researchers will focus on new biological aspects of the circular RNA molecules, with the aim of revealing why humans have a stronger and more complex brain than other organisms with a similar number of genes,” Stamm says.

Prof. Sperling, a world-renowned expert in RNA processing, is seeking to understand how circular RNA is created by the splicing machinery in cells, to analyze when this occurs and how it is regulated in the brain.

According to Sperling, “If we do find that we have new proteins, this opens up a completely new research field with essential functions for the human brain.” Such a discovery may have wide implications, for example, on the detection of genetic materials correlated with schizophrenia, epilepsy, autism, or neurological disease.”

The hypothesis is that the new proteins, translated from these specific circular RNAs, substantially increase molecular complexity, which improves brain functions. “Do circular RNAs code for proteins? Do these proteins function? Can they be found in the brain? This is what we are analyzing. It has never been looked at,” Stamm says.

As part of the three-year project, there will be annual two-week RNA biology courses held in the summer at Hebrew University in Jerusalem led by Stamm and Sperling. Students from both universities will have theoretical lectures and do hands-on experiments during the course.

Research reported in this publication was supported by the National Science Foundation under Award Number 2221921, and United States-Israel Binational Science Foundation under Award Number 2022602.