|Amelioration of Fragile X Syndrome via inhibition of the synaptic RNA-binding protein CPEB1
By Natalie Farny and Joel Richter, 4/30/2010
The connections in our brains are constantly changing. As we interact with our environment and with each other, the connections between our neurons are remodeled so that we can retain these interactions as learning and memory. At a molecular level, the brain accomplishes this remodeling in part by making new proteins (a process known as protein synthesis) at the specific sites where our neurons interact with each other (known as synapses). The development of new synaptic connections and the pruning away of old ones through the process of protein synthesis is the molecular basis for learning, memory, and behavior. The process of synaptic remodeling, of strengthening and weakening of connections between neurons, is known as synaptic plasticity. Defects in synaptic plasticity are seen in many neurological disorders, including Fragile X Syndrome, which result in problems with learning and behavior.
There are many proteins required for the regulation of protein synthesis in synapses. One such protein is known as FMRP, the product of the Fragile X mental retardation gene. In individuals suffering from Fragile X Syndrome, FMRP is not present to regulate protein synthesis in neurons, and synaptic plasticity is negatively affected.
In our lab at the University of Massachusetts Medical School, we study another protein that is important for regulating protein synthesis in synapses, known as CPEB. We noted that CPEB and FMRP seem to have opposite effects on protein synthesis: FMRP is generally thought to inhibit protein synthesis, and CPEB is thought to activate protein synthesis. These two proteins may thus be important for maintaining a balance of protein synthesis at the synapse; in the absence of one of these proteins, the activity of the other becomes excessive, and defects of synaptic plasticity will result. We hypothesize that when FMRP is absent, reducing or eliminating the activity of CPEB could correct this imbalance of protein synthesis and restore normal synaptic plasticity.
To test our hypothesis, we bred mice lacking FMRP with mice lacking CPEB, to create mice that are missing both genes (“double knockout” mice). In an exciting series of experiments, we have seen that certain defects in synaptic plasticity that are characteristic of FMRP null mice are corrected in the double knockout mice. Currently, we are working to examine whether other behavioral and molecular phenotypes of Fragile X mice are corrected in our double knockout mice.
Our preliminary results suggest that decreasing the activity of CPEB in the brain could be a useful therapeutic strategy for treating Fragile X Syndrome. We are currently designing a screen to identify drug compounds that inhibit the activity of CPEB. Our hypothesis is that inhibiting CPEB activity in the brain could restore the balance of protein synthesis in the brains of both Fragile X mice and humans, similar to the corrective effects we see in double knockout mice. We plan to screen hundreds of thousands of compounds to find a drug that inhibits CPEB, which could one day be used as a new treatment for the Fragile X Syndrome.