Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression.
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.
Hou
Lingfei
L
Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Antion
Marcia D
MD
Hu
Daoying
D
Spencer
Corinne M
CM
Paylor
Richard
R
Klann
Eric
E
D000818:Animals; D000831:Animals, Newborn; D000841:Anisomycin / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D007976:Leupeptins / Q000494:pharmacology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
D000841:Anisomycin; D001565:Benzoates; D015853:Cysteine Proteinase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D005998:Glycine; D007976:Leupeptins; D008734:Methoxyhydroxyphenylglycol; D008869:Microtubule-Associated Proteins; D046988:Proteasome Endopeptidase Complex; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse; C079240:Mtap2 protein, mouse; C079694:alpha-methyl-4-carboxyphenylglycine; C121465:6-methyl-2-(phenylethynyl)pyridine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C010117:3,4-dihydroxyphenylglycol