Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses
- Ivan Jeanne Weiler*,†,‡,
- Chad C. Spangler*,†,
- Anna Y. Klintsova*,
- Aaron W. Grossman*,§,
- Soong Ho Kim*,§,
- Valerie Bertaina-Anglade*,
- Hooma Khaliq*,
- Froukje E. de Vries*,
- Femke A. E. Lambers*,
- Fatima Hatia*,
- Christine K. Base*, and
- William T. Greenough*,¶
- *Beckman Institute, §Neuroscience Program, and ¶Departments of Psychology, Psychiatry, and Cell and Structural Biology, University of Illinois at Urbana–Champaign, Urbana, IL 61801
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Contributed by William T. Greenough, October 13, 2004
Abstract
Fragile X mental retardation is caused by absence of the RNA-binding protein fragile X mental retardation protein (FMRP), encoded by the FMR1 gene. There is increasing evidence that FMRP regulates transport and modulates translation of some mRNAs. We studied neurotransmitter-activated synaptic protein synthesis in fmr1-knockout mice. Synaptoneurosomes from knockout mice did not manifest accelerated polyribosome assembly or protein synthesis as it occurs in wild-type mice upon stimulation of group I metabotropic glutamate receptors. Direct activation of protein kinase C did not compensate in the knockout mouse, indicating that the FMRP-dependent step is further along the signaling pathway. Visual cortices of young knockout mice exhibited a lower proportion of dendritic spine synapses containing polyribosomes than did the cortices of wild-type mice, corroborating this finding in vivo. This deficit in rapid neurotransmitter-controlled local translation of specific proteins may contribute to morphological and functional abnormalities observed in patients with fragile X syndrome.
Footnotes
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↵ ‡ To whom correspondence should be addressed. E-mail: i-weiler{at}uiuc.edu.
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↵ † I.J.W. and C.C.S. contributed equally to this work.
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Author contributions: I.J.W., C.C.S., A.Y.K., A.W.G., S.H.K., and W.T.G. designed research; I.J.W., C.C.S., A.Y.K., A.W.G., S.H.K., V.B.-A., H.K., F.E.d.V., F.A.E.L., F.H., and C.K.B. performed research; A.W.G. analyzed data; and I.J.W., A.W.G., and W.T.G. wrote the paper.
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Abbreviations: KO, knockout; mGluR, metabotropic glutamate receptor; PRA, polyribosomal aggregate; OAG, 1-oleoyl-2-acetyl-sn-glycerol; DHPG, (S)3,5-dihydroxyphenylglycine; P-mRNA, polyribosomal mRNA.
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See Commentary on page 17329.
- Copyright © 2004, The National Academy of Sciences
