A 3′ untranslated region variant in FMR1 eliminates neuronal activity-dependent translation of FMRP by disrupting binding of the RNA-binding protein HuR
| Autor: | Joshua A. Suhl, Ravi S. Muddashetty, Gary J. Bassell, Stephen T. Warren, Jeannie Visootsak, Bart R. Anderson, Marius F. Ifrim |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Untranslated region congenital hereditary and neonatal diseases and abnormalities RNA Stability Molecular Sequence Data Electrophoretic Mobility Shift Assay RNA-binding protein Biology ELAV-Like Protein 1 Fragile X Mental Retardation Protein Mice Genes Reporter Tandem Mass Spectrometry medicine Protein biosynthesis Animals Humans Biotinylation Electrophoretic mobility shift assay RNA Messenger Luciferases 3' Untranslated Regions Alleles Cells Cultured Neurons Multidisciplinary Base Sequence Three prime untranslated region RNA Dendrites medicine.disease Molecular biology FMR1 nervous system diseases Fragile X syndrome PNAS Plus Receptors Glutamate Genetic Loci Protein Biosynthesis Synapses Sequence Alignment Protein Binding Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 112 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1514260112 |
| Popis: | Fragile X syndrome is a common cause of intellectual disability and autism spectrum disorder. The gene underlying the disorder, fragile X mental retardation 1 (FMR1), is silenced in most cases by a CGG-repeat expansion mutation in the 5' untranslated region (UTR). Recently, we identified a variant located in the 3'UTR of FMR1 enriched among developmentally delayed males with normal repeat lengths. A patient-derived cell line revealed reduced levels of endogenous fragile X mental retardation protein (FMRP), and a reporter containing a patient 3'UTR caused a decrease in expression. A control reporter expressed in cultured mouse cortical neurons showed an expected increase following synaptic stimulation that was absent when expressing the patient reporter, suggesting an impaired response to neuronal activity. Mobility-shift assays using a control RNA detected an RNA-protein interaction that is lost with the patient RNA, and HuR was subsequently identified as an associated protein. Cross-linking immunoprecipitation experiments identified the locus as an in vivo target of HuR, supporting our in vitro findings. These data suggest that the disrupted interaction of HuR impairs activity-dependent translation of FMRP, which may hinder synaptic plasticity in a clinically significant fashion. |
| Databáze: | OpenAIRE |
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