Professor of Biology Robert Reenan has found a surprising connection between two perplexingly different biochemical processes, pushing researchers one step closer in the search for a genetic basis to neurological disease.
Reenan and Thomas Jongens, associate professor of genetics at Penn, found that two seemingly different proteins physically interact to affect a process called RNA editing. Their study was published in Nature Neuroscience Oct. 30.
Previously, Fragile X Mental Retardation protein, FMR protein, was thought to have only two essential functions in the human body.
The protein can associate with ribosomes and determine the speed of protein formation, Reenan said. It is also involved in the transport of mRNAs from cells to synapses, where electrical signals are sent from neuron to neuron, he said.
Fragile X syndrome results from a loss or a decreased amount of the FMR protein, Reenan said. Autism spectrum disorders may be linked to this protein.
About five years ago, Jongens' lab discovered that when FMR was removed from the cell, an RNA protein called ADAR — adenosine deaminase acting on RNA — came along with it.
ADAR is an enzyme that chemically modifies RNA through a process known as RNA editing.
"Through some very interesting dynamics, the mRNA actually folds on itself to form a structure that the ADAR enzyme recognizes," Reenan said.
RNA, like DNA, is made of sequences of four different nucleic acid bases. ADAR effectively changes one of those bases to a form recognized as another. More specifically, adenosine becomes inosine, which is read by the cell as a guanine, one of the four nucleic acid bases. This results in a change in the genetic code, and an affected gene can thus make many more proteins, Reenan said.
The scientific community has long wondered why humans and fruit flies have a similar number of genes when humans are far more complex organisms. Reenan's conclusion provides an explanation for this gene number paradox.
The premise of the project was to see if there was a connection between the FMR gene function — that associated with protein formation and the deliverance of mRNA to synapses — and output for RNA editing because of interaction between the proteins, he said.
"Sure enough, we found that if you perturb FMR, then you are actually perturbing RNA editing," Reenan said. "Now we have a factor that clearly regulates RNA editing."
When humans and fruit flies have mutations of these RNA binding proteins, neurological and behavioral defects often result, Reenan said. Fruit flies with no ADAR survived until adulthood but were "genetically dead" and lacked much motor control, he said.
Though this study does not give much information as to treatment of diseases associated with ADAR and FMR, it does give researchers a starting point.
"It gives us a direction to look in," said Reenan. "If we were previously looking where the light is, this at least expands the light — it gives us more places to look."
The next step is to figure out how the entire process of RNA regulation works. Researchers must identify which mRNA associated with ADAR and FMR are connected to disease symptoms.
"It's the story that keeps us in business," said Reenan. "The more carefully we look, the more complicated things get. But eventually, we will have a greater understanding of this very complex set of phenomena."
