Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome.
The Osterweil lab has identified a potential new strategy for treating fragile x syndrome. As excessive protein synthesis is pathological in the fragile X brain, it is thought that over-produced proteins should be downregulated. In their study, they found that one of the most over-produced proteins, muscarinic receptor M4, is something that is potentially protective. By boosting the function of M4 it can correct multiple phenotypes in the fragile X mouse model, including seizures. This suggests that some of the over-produced proteins in the fragile X brain should be enhanced rather than inhibited. Researchers in the lab used cell type-specific Translating Ribosome Affinity Purification (TRAP) to isolate mistranslating mRNAs in specific neuron populations. This allowed us to identify M4 over-translation.
This study shows that not all over-translated proteins in the fragile X brain are bad. In fact, some may be important targets for enhancement rather than inhibition. In this case, M4 positive allosteric modulators (PAMs) may be a novel therapeutic option for fragile X. The lab will continue to identify the role of mis-translating mRNAs, and determine how they affect altered function in the fragile X brain, and also perform additional experiments to assess whether M4 PAMs can correct cognitive phenotypes in the fragile X rat and mouse models.
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Wellcome Trust/Royal Society ( Sir Henry Dale Fellowship)
MRC (New Investigator Research Grant)
FRAXA (Postdoctoral fellowship for Steph Barnes)
TSA (Postdoctoral fellowship for Sophie Thomson)