Dynamic Translational and Proteasomal Regulation of Fragile X Mental Retardation Protein Controls mGluR-Dependent Long-Term Depression

Lingfei Hou, Marcia D. Antion, Daoying Hu, Corinne M. Spencer, Richard Paylor, Eric Klann

Research output: Contribution to journalArticle

Abstract

Genetic deletion of fragile X mental retardation protein (FMRP) has been shown to enhance mGluR-dependent long-term depression (LTD). Herein, we demonstrate that mGluR-LTD induces a transient, translation-dependent increase in FMRP that is rapidly degraded by the ubiquitin-proteasome pathway. Moreover, proteasome inhibitors abolished mGluR-LTD, and LTD was absent in mice that overexpress human FMRP. Neither translation nor proteasome inhibitors blocked the augmentation of mGluR-LTD in FMRP-deficient mice. In addition, mGluR-LTD is associated with rapid increases in the protein levels of FMRP target mRNAs in wild-type mice. Interestingly, the basal levels of these proteins were elevated and their synthesis was improperly regulated during mGluR-LTD in FMRP-deficient mice. Our findings indicate that hippocampal mGluR-LTD requires the rapid synthesis and degradation of FMRP and that mGluR-LTD triggers the synthesis of FMRP binding mRNAs. These findings indicate that the translation, ubiquitination, and proteolysis of FMRP functions as a dynamic regulatory system for controlling synaptic plasticity.

Original languageEnglish (US)
Pages (from-to)441-454
Number of pages14
JournalNeuron
Volume51
Issue number4
DOIs
StatePublished - Aug 17 2006

Fingerprint

Fragile X Mental Retardation Protein
Proteasome Inhibitors
Messenger RNA
Neuronal Plasticity
Ubiquitination
Proteasome Endopeptidase Complex
Ubiquitin
Protein Binding
Proteolysis
Proteins

Keywords

  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Dynamic Translational and Proteasomal Regulation of Fragile X Mental Retardation Protein Controls mGluR-Dependent Long-Term Depression. / Hou, Lingfei; Antion, Marcia D.; Hu, Daoying; Spencer, Corinne M.; Paylor, Richard; Klann, Eric.

In: Neuron, Vol. 51, No. 4, 17.08.2006, p. 441-454.

Research output: Contribution to journalArticle

Hou, Lingfei ; Antion, Marcia D. ; Hu, Daoying ; Spencer, Corinne M. ; Paylor, Richard ; Klann, Eric. / Dynamic Translational and Proteasomal Regulation of Fragile X Mental Retardation Protein Controls mGluR-Dependent Long-Term Depression. In: Neuron. 2006 ; Vol. 51, No. 4. pp. 441-454.
@article{3eb99785aea64974a352eee7c0587957,
title = "Dynamic Translational and Proteasomal Regulation of Fragile X Mental Retardation Protein Controls mGluR-Dependent Long-Term Depression",
abstract = "Genetic deletion of fragile X mental retardation protein (FMRP) has been shown to enhance mGluR-dependent long-term depression (LTD). Herein, we demonstrate that mGluR-LTD induces a transient, translation-dependent increase in FMRP that is rapidly degraded by the ubiquitin-proteasome pathway. Moreover, proteasome inhibitors abolished mGluR-LTD, and LTD was absent in mice that overexpress human FMRP. Neither translation nor proteasome inhibitors blocked the augmentation of mGluR-LTD in FMRP-deficient mice. In addition, mGluR-LTD is associated with rapid increases in the protein levels of FMRP target mRNAs in wild-type mice. Interestingly, the basal levels of these proteins were elevated and their synthesis was improperly regulated during mGluR-LTD in FMRP-deficient mice. Our findings indicate that hippocampal mGluR-LTD requires the rapid synthesis and degradation of FMRP and that mGluR-LTD triggers the synthesis of FMRP binding mRNAs. These findings indicate that the translation, ubiquitination, and proteolysis of FMRP functions as a dynamic regulatory system for controlling synaptic plasticity.",
keywords = "HUMDISEASE, MOLNEURO",
author = "Lingfei Hou and Antion, {Marcia D.} and Daoying Hu and Spencer, {Corinne M.} and Richard Paylor and Eric Klann",
year = "2006",
month = "8",
day = "17",
doi = "10.1016/j.neuron.2006.07.005",
language = "English (US)",
volume = "51",
pages = "441--454",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "4",

}

TY - JOUR

T1 - Dynamic Translational and Proteasomal Regulation of Fragile X Mental Retardation Protein Controls mGluR-Dependent Long-Term Depression

AU - Hou, Lingfei

AU - Antion, Marcia D.

AU - Hu, Daoying

AU - Spencer, Corinne M.

AU - Paylor, Richard

AU - Klann, Eric

PY - 2006/8/17

Y1 - 2006/8/17

N2 - Genetic deletion of fragile X mental retardation protein (FMRP) has been shown to enhance mGluR-dependent long-term depression (LTD). Herein, we demonstrate that mGluR-LTD induces a transient, translation-dependent increase in FMRP that is rapidly degraded by the ubiquitin-proteasome pathway. Moreover, proteasome inhibitors abolished mGluR-LTD, and LTD was absent in mice that overexpress human FMRP. Neither translation nor proteasome inhibitors blocked the augmentation of mGluR-LTD in FMRP-deficient mice. In addition, mGluR-LTD is associated with rapid increases in the protein levels of FMRP target mRNAs in wild-type mice. Interestingly, the basal levels of these proteins were elevated and their synthesis was improperly regulated during mGluR-LTD in FMRP-deficient mice. Our findings indicate that hippocampal mGluR-LTD requires the rapid synthesis and degradation of FMRP and that mGluR-LTD triggers the synthesis of FMRP binding mRNAs. These findings indicate that the translation, ubiquitination, and proteolysis of FMRP functions as a dynamic regulatory system for controlling synaptic plasticity.

AB - Genetic deletion of fragile X mental retardation protein (FMRP) has been shown to enhance mGluR-dependent long-term depression (LTD). Herein, we demonstrate that mGluR-LTD induces a transient, translation-dependent increase in FMRP that is rapidly degraded by the ubiquitin-proteasome pathway. Moreover, proteasome inhibitors abolished mGluR-LTD, and LTD was absent in mice that overexpress human FMRP. Neither translation nor proteasome inhibitors blocked the augmentation of mGluR-LTD in FMRP-deficient mice. In addition, mGluR-LTD is associated with rapid increases in the protein levels of FMRP target mRNAs in wild-type mice. Interestingly, the basal levels of these proteins were elevated and their synthesis was improperly regulated during mGluR-LTD in FMRP-deficient mice. Our findings indicate that hippocampal mGluR-LTD requires the rapid synthesis and degradation of FMRP and that mGluR-LTD triggers the synthesis of FMRP binding mRNAs. These findings indicate that the translation, ubiquitination, and proteolysis of FMRP functions as a dynamic regulatory system for controlling synaptic plasticity.

KW - HUMDISEASE

KW - MOLNEURO

UR - http://www.scopus.com/inward/record.url?scp=33746866693&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746866693&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2006.07.005

DO - 10.1016/j.neuron.2006.07.005

M3 - Article

VL - 51

SP - 441

EP - 454

JO - Neuron

JF - Neuron

SN - 0896-6273

IS - 4

ER -