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Cited by 280Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchRNA and protein synthesis mechanisms

The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95

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Todd, Peter K., Mack, Kenneth J., Malter, James S.·2003·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2336265100PMC PMC283599
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Abstract

Fragile X syndrome (FXS) is a common inherited cause of mental retardation resulting from the absence of the fragile X mental retardation protein (FMRP). FMRP is thought to regulate the translation of target mRNAs, including its own transcript. Here we show that the levels of FMRP are rapidly up-regulated in primary cortical neurons in response to the type-I metabotropic glutamate receptor (mGluR) agonist S-3,5-dihydrophenylglycine. These changes require new protein synthesis but not transcription and are specific to mGluR activation. We also demonstrate that the mRNA for PSD-95, a scaffolding protein involved in synaptic plasticity, contains a highly conserved canonical binding site for FMRP within its 3' UTR. Furthermore, PSD-95 is rapidly translated in response to S-3,5-dihydrophenylglycine. Finally, we show that these mGluR-dependent changes in PSD-95 expression are lost in neurons derived from FMRP knockout mice, a model of FXS. Taken together, these studies suggest that FMRP is required for mGluR-dependent translation of PSD-95 and provide insights into the pathophysiology of FXS.

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  • DHPG stimulates dendritic translation of FMRP.

    “In fact, in both assays there was more FMRP immunoprecipitated from the DHPG-treated WT SNs, which is in agreement with previous reports that DHPG stimulates the dendritic translation of FMRP [22,39].”

    From FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein (2007) · cites this paper as [22]

    The Results (page not available) show that DHPG increased FMRP in cortical neurons and that a protein-synthesis inhibitor blocked the increase. The same section reports DHPG-induced FMRP translation in synaptoneurosomes, but the paper does not establish that the new FMRP was translated specifically within dendrites. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • FMRP is required for type 1 mGluR-dependent translation of synaptic proteins, including FMRP and PSD-95.

    “FMRP is required for type 1 metabotropic glutamate receptor (mGluR)–dependent translation of synaptic proteins, including FMRP and postsynaptic density 95 (PSD-95) [21,22].”

    From FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein (2007) · cites this paper as [22]

    The Discussion reports that type-I mGluR activation rapidly induces translation of both FMRP and PSD-95, while the knockout result supports a requirement for FMRP in PSD-95 translation. The Results also show mGluR-dependent production of FMRP, but the paper does not establish that FMRP is required for its own mGluR-dependent translation. Page numbers are not available in the supplied passages. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • mGluR activation rapidly derepresses APP synthesis.

    “mGluR activation rapidly derepresses APP synthesis as shown for FMRP and PSD-95 [21,22].”

    From FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein (2007) · cites this paper as [22]

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Cited by

Sorted by citations

Authors
Todd, P. K., Mack, K. J., & Malter, J. S.
Affiliations
University of Wisconsin–Madison (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2003-11-12
Volume
100
Issue
24
Pages
14374-14378
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2336265100
PMC
PMC283599
OpenAlex
W2149580098
Cited by
280
References
4
Citations by year
2025: 2 · 2024: 6 · 2023: 5 · 2022: 6 · 2021: 7 · 2020: 3 · 2019: 13 · 2018: 9 · 2017: 8 · 2016: 4 · 2015: 10 · 2014: 17 · 2013: 11 · 2012: 19
FWCI
8.31
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • FRAXA Research Foundation
  • National Institutes of Health
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
fragile X syndrome, FMRP, PSD-95, 3' UTR binding sites, mRNA translation regulation, cortical neurons, synaptic plasticity
MeSH terms
Disks Large Homolog 4 Protein, Animals, Base Sequence, Binding Sites, Fragile X Syndrome, Glycine, Membrane Proteins, Mice, Inbred C57BL, Nerve Tissue Proteins, Resorcinols, RNA, Messenger, Sequence Homology, Nucleic Acid, Protein Biosynthesis, RNA-Binding Proteins, Conserved Sequence, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Mice, Knockout, Intracellular Signaling Peptides and Proteins, Mice, Rats, Guanylate Kinases, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1

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