Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome.
Sophie R. Thomson, Sang S. Seo, Stephanie A. Barnes,, Susana R. Louros, Melania Muscas, Owen Dando, Caoimhe Kirby, David J.A. Wyllie, Giles E. Hardingham, Peter C. Kind, Emily K. Osterweil.
www.Osterlab.org
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.
Read the full Paper Here
Collaborators: Profs Peter Kind, Giles Hardingham and David Wyllie.
Funders:
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)
