Dephosphorylation-Induced Ubiquitination and Degradation of FMRP in Dendrites: A Role in Immediate Early mGluR-Stimulated Translation
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Fragile X syndrome is caused by the loss of fragile X mental retardation protein (FMRP), which represses and reversibly regulates the translation of a subset of mRNAs in dendrites. Protein synthesis can be rapidly stimulated by mGluR-induced and protein phosphatase 2a (PP2A)-mediated dephosphorylation of FMRP, which is coupled to the dissociation of FMRP and target mRNAs from miRNA-induced silencing complexes. Here, we report the rapid ubiquitination and ubiquitin proteasome system (UPS)-mediated degradation of FMRP in dendrites upon DHPG (3,5-dihydroxyphenylglycine) stimulation in cultured rat neurons. Using inhibitors to PP2A and FMRP phosphomutants, degradation of FMRP was observed to depend on its prior dephosphorylation. Translational induction of an FMRP target, postsynaptic density-95 mRNA, required both PP2A and UPS. Thus, control of FMRP levels at the synapse by dephosphorylation-induced and UPS-mediated degradation provides a mode to regulate protein synthesis.
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Upon receptor activation, the FMRP-mediated translational block is released, possibly due to changes in phosphorylation status, and protein synthesis ensues.
“Upon receptor activation, the FMRPmediated translational block is released, possibly due to changes (86) in its phosphorylation status, and protein synthesis can ensue.”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [86]
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Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics
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- Authors
- Nalavadi, V. C., Muddashetty, R. S., Gross, C., & Bassell, G. J.
- Affiliations
- Emory University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-02-22
- Volume
- 32
- Issue
- 8
- Pages
- 2582-2587
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3427762
- OpenAlex
- W2043378710
- Cited by
- 128
- References
- 33
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 12 · 2019: 12 · 2018: 11 · 2017: 8 · 2016: 11 · 2015: 15 · 2014: 16 · 2013: 8 · 2012: 4
- FWCI
- 8.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R01MH085617, MH086405)
- National Institute of Neurological Disorders and Stroke (R01NS051127, P30NS055077)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD001799, P30HD024064)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- FMRP, fragile X syndrome, ubiquitination, ubiquitin-proteasome system, protein degradation, dephosphorylation, protein phosphatase 2A, dendritic translation, DHPG, miRNA-induced silencing complex, synaptic protein synthesis
- MeSH terms
- Bortezomib, Disks Large Homolog 4 Protein, Analysis of Variance, Animals, Boronic Acids, Cells, Cultured, Dendrites, Embryo, Mammalian, Enzyme Inhibitors, Female, Gene Expression Regulation, Hippocampus, Leupeptins, Male, Membrane Proteins, Methoxyhydroxyphenylglycol, Mutation, Neurons, Phosphoprotein Phosphatases, Phosphorylation, Pyrazines, RNA, Messenger, Serine, Synapses, Transfection, Protein Biosynthesis, Signal Transduction, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Okadaic Acid, Drosophila Proteins, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Green Fluorescent Proteins, Rats, Fragile X Messenger Ribonucleoprotein 1, Ubiquitination
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