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FMRP Mediates mGluR(5)-Dependent Translation of Amyloid Precursor Protein

Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Aβ) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding...

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Detalles Bibliográficos
Autores principales: Westmark, Cara J, Malter, James S
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808499/
https://www.ncbi.nlm.nih.gov/pubmed/17298186
http://dx.doi.org/10.1371/journal.pbio.0050052
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author Westmark, Cara J
Malter, James S
author_facet Westmark, Cara J
Malter, James S
author_sort Westmark, Cara J
collection PubMed
description Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Aβ) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding protein whose expression is lost in fragile X syndrome. Here we show that FMRP binds to the coding region of APP mRNA at a guanine-rich, G-quartet–like sequence. Stimulation of cortical synaptoneurosomes or primary neuronal cells with the metabotropic glutamate receptor agonist DHPG increased APP translation in wild-type but not fmr-1 knockout samples. APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment. Soluble Aβ(40) or Aβ(42) levels were significantly higher in multiple strains of fmr-1 knockout mice compared to wild-type controls. Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome.
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spelling pubmed-18084992007-03-14 FMRP Mediates mGluR(5)-Dependent Translation of Amyloid Precursor Protein Westmark, Cara J Malter, James S PLoS Biol Research Article Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Aβ) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding protein whose expression is lost in fragile X syndrome. Here we show that FMRP binds to the coding region of APP mRNA at a guanine-rich, G-quartet–like sequence. Stimulation of cortical synaptoneurosomes or primary neuronal cells with the metabotropic glutamate receptor agonist DHPG increased APP translation in wild-type but not fmr-1 knockout samples. APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment. Soluble Aβ(40) or Aβ(42) levels were significantly higher in multiple strains of fmr-1 knockout mice compared to wild-type controls. Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome. Public Library of Science 2007-03 2007-02-13 /pmc/articles/PMC1808499/ /pubmed/17298186 http://dx.doi.org/10.1371/journal.pbio.0050052 Text en © 2007 Westmark and Malter. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Westmark, Cara J
Malter, James S
FMRP Mediates mGluR(5)-Dependent Translation of Amyloid Precursor Protein
title FMRP Mediates mGluR(5)-Dependent Translation of Amyloid Precursor Protein
title_full FMRP Mediates mGluR(5)-Dependent Translation of Amyloid Precursor Protein
title_fullStr FMRP Mediates mGluR(5)-Dependent Translation of Amyloid Precursor Protein
title_full_unstemmed FMRP Mediates mGluR(5)-Dependent Translation of Amyloid Precursor Protein
title_short FMRP Mediates mGluR(5)-Dependent Translation of Amyloid Precursor Protein
title_sort fmrp mediates mglur(5)-dependent translation of amyloid precursor protein
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808499/
https://www.ncbi.nlm.nih.gov/pubmed/17298186
http://dx.doi.org/10.1371/journal.pbio.0050052
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