FMRP mediates mGluR5-dependent translation of amyloid precursor protein.

Cara J. Westmark, James S. Malter

Research output: Contribution to journalArticle

176 Citations (Scopus)

Abstract

Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Abeta) 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 Abeta40 or Abeta42 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.

Original languageEnglish (US)
JournalPLoS Biology
Volume5
Issue number3
DOIs
StatePublished - Mar 2007

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Fragile X Mental Retardation Protein
Amyloid beta-Protein Precursor
amyloid
translation (genetics)
Fragile X Syndrome
Messenger RNA
Metabotropic Glutamate Receptors
Amyloid
Alzheimer Disease
proteins
Excitatory Amino Acid Agonists
Guanine
Protein Biosynthesis
Knockout Mice
Synaptic Transmission
Synapses
Alzheimer disease
Carrier Proteins
Brain
Chemical activation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)

Cite this

FMRP mediates mGluR5-dependent translation of amyloid precursor protein. / Westmark, Cara J.; Malter, James S.

In: PLoS Biology, Vol. 5, No. 3, 03.2007.

Research output: Contribution to journalArticle

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