A Radar for ADAR: Altered Gene Tracks RNA Editing in Neurons

Biologists already know that errors in transcribing RNA from DNA can lead to improper gene expression in the nervous system and might contribute to diseases such as epilepsy, suicidal depression, and schizophrenia.

Dec 26 2011 --- To track what they can't see, pilots look to the green glow of the radar screen. Now biologists monitoring gene expression, individual variation, and disease have a glowing green indicator of their own: Brown University biologists have developed a "radar" for tracking ADAR, a crucial enzyme for editing RNA in the nervous system.

The advance gives scientists a way to view when and where ADAR is active in a living animal and how much of it is operating. In experiments in fruit flies described in the journal Nature Methods, the researchers show surprising degrees of individual variation in ADAR's RNA editing activity in the learning and memory centers of the brains of individual flies.

"We designed this molecular reporter to give us a fluorescent readout from living organisms," said Robert Reenan, professor of biology and senior author of the paper, which appears Dec. 25, 2011. "When it comes to gene expression and regulation, the devil is in the details."

Biologists already know that errors in transcribing RNA from DNA can lead to improper gene expression in the nervous system and might contribute to diseases such as epilepsy, suicidal depression, and schizophrenia. More recently they've gathered evidence that ADAR is associated with disease. For instance in a study in Nature Neuroscience two months ago, Reenan and colleagues at the University of Pennsylvania described profound connections between ADAR and a model of Fragile X mental retardation in fruit flies.

Reenan said that using the new "reporter" tool to look for correlations between ADAR activity levels and behavior or disease might yield new insights into how RNA editing errors lead to such variations. But he also speculated that the mechanics of how he and his research group created the fluorescent ADAR tracking system could be adapted to someday allow therapies based on targeted RNA repair. Their reporter works by requiring ADAR to fix a purposely broken individual letter of RNA on an engineered gene.

"We're actually repairing RNA at the level of a single informational bit, or nucleotide," Reenan said. "Here we've shown we can take a mutant version of a gene and restore its function, but at the level of RNA rather than DNA."