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Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome
Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu(1/5)) is a core pathophysiology of fragile X syndrome (FX); however, the differentially translating mRNAs that contribute to altered neural function are not known. We used translating ribosome affinity purificati...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548955/ https://www.ncbi.nlm.nih.gov/pubmed/28772121 http://dx.doi.org/10.1016/j.neuron.2017.07.013 |
Sumario: | Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu(1/5)) is a core pathophysiology of fragile X syndrome (FX); however, the differentially translating mRNAs that contribute to altered neural function are not known. We used translating ribosome affinity purification (TRAP) and RNA-seq to identify mistranslating mRNAs in CA1 pyramidal neurons of the FX mouse model (Fmr1(−/y)) hippocampus, which exhibit exaggerated mGlu(1/5)-induced long-term synaptic depression (LTD). In these neurons, we find that the Chrm4 transcript encoding muscarinic acetylcholine receptor 4 (M(4)) is excessively translated, and synthesis of M(4) downstream of mGlu(5) activation is mimicked and occluded. Surprisingly, enhancement rather than inhibition of M(4) activity normalizes core phenotypes in the Fmr1(−/y), including excessive protein synthesis, exaggerated mGluR-LTD, and audiogenic seizures. These results suggest that not all excessively translated mRNAs in the Fmr1(−/y) brain are detrimental, and some may be candidates for enhancement to correct pathological changes in the FX brain. |
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