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Genetic mutation found to restore translational balance in mice. A research result suggests a prime cause of Fragile X syndrome may be an over production of protein in the brain. If restoration of this balance is possible, normal neurologic function might be restored.
A biological quirk promises to provide researchers with a new approach for studying and potentially treating Fragile X syndrome. Scientists at the University of Massachusetts Medical School (UMMS) found that knocking out a gene important to messenger RNA (mRNA) in neurons, restores memory deficits, reducing behavioral symptoms in a mouse model of the disease.
These results, published in Nature Medicine, suggest that the prime cause of the Fragile X syndrome may be a translational imbalance resulting in elevated protein production in the brain. Restoration of this balance may be necessary for normal neurologic function.
Fragile X syndrome, the most common form of inherited mental retardation and the most frequent single-gene cause of autism, is a genetic condition resulting from a CGG repeat expansion in the DNA sequence of the Fragile X (Fmr1) gene required for normal neurological development.
People with Fragile X suffer from intellectual disability as well as behavioral and learning challenges. Depending on the length of the CGG repeat, intellectual disabilities can range from mild to severe.
While scientists have identified the genetic mutation that causes Fragile X, on a molecular level they still don't know much about how the disease works or what precisely goes wrong in the brain as a result.
From Frog Egg to Fragile X
Dr. Richter has been studying for years how translation—the process by which cellular ribosomes create proteins—went from dormant to active in frog eggs. He discovered that RNA binding protein CPEB is key in controlling translation. In 1998, he found CPEB in the rodent brain playing an important role in regulating how synapses talk to each other. At this point, his work began to move from exploring the role of CPEB in frog development to how CPEB impacts learning and memory.
A serendipitous research symposium with colleagues at Cold Spring Harbor got him thinking about CPEB and Fragile X syndrome.
"Here I was, an outsider, a molecular biologist who had worked for years with frog eggs, in the same room with neurobiologists and neurologists, when they started talking about Fragile X syndrome and translational activity," said Richter. "It got me thinking that the CPEB protein might be a path to restoring the translational imbalance they were discussing."
To test his hypothesis, Richter developed a double knockout mouse model that lacked both the FMRP gene that caused Fragile X and the CPEB gene. When they began measuring for Fragile X pathologies what they found was almost too good to be true.
"We measured a host of factors, biochemical, morphological, electrophysiological and behavioral phenotypes," said Richter. "And we kept finding the same thing. By knocking out both the FMRP and CPEB genes we were able to restore levels of protein synthesis to normal and corrected the disease characteristics of the Fragile X mice, making them almost indistinguishable from wild type mice."
Most importantly, tests to evaluate short-term memory in the double knockout mice also showed normal results with no indications of Fragile X pathology. This suggested an experiment to test whether CPEB might be a potential therapeutic target for Fragile X to benefit patients. Richter and colleagues took adult Fragile X mice and injected a lentivirus that expresses a small RNA to knock down CPEB in the hippocampus, which is a brain region that is important for short-term memory. Subsequent tests showed improved short-term memory in these mice, indicating that at least this one characteristic of Fragile X syndrome, which is generally thought to be a developmental disorder, can be reversed in adults.
The next step for Richter and colleagues is to determine which, of the more than 300 mRNAs that both CPEB and FMRP bind to, contribute to Fragile X syndrome and how. They will also begin looking at small molecules and other avenues that, like the ablation of the CPEB protein, might be able to slow down the synthesis of protein.
"This is another, great example of how basic science translates to human disease. If we had started out looking at the human brain, not knowing about the CPEB protein and its role in translational activity, we wouldn't have had any idea where to start or what to look for. But because we started out in the frog, where things are much easier to see, and because more often than not these processes are conserved, we've learned something new and totally unexpected that may have a profound impact on human disease."
About the University of Massachusetts Medical School
Original press release:http://www.umassmed.edu/news/2013/research/two-genetic-wrongs-make-a-biochemical-right.aspx