At first blush, Alzheimer disease and fragile X syndrome may appear as chalk and cheese, since the former is a neurodegenerative disease and the latter a developmental disorder. However, both are characterized by synaptic pathology and as exemplified by a paper in this month’s PLoS, the two may have a deeper connection than that. Cara Westmark and James Malter, University of Wisconsin, Madison, reported that fragile X mental retardation protein (FMRP), the product of the fragile X gene, regulates translation of amyloid-β precursor protein (APP). They found that in primary neurons FMRP binds to APP mRNA and prevents its translation. This repression can be relieved by activation of metabotropic glutamate receptors. The finding suggests that overproduction of APP, and hence its proteolytic derivative amyloid-β, may be a common feature of both diseases.

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Cara Westmark led this Webinar on 21 March 2007. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.


Background Text
By Cara Westmark

Fragile X syndrome (FXS) is the most common form of inherited mental retardation with a frequency of 1 in 4,000 males and 1 in 8,000 females. The disorder results from a mutation in a single gene, fmr-1, located on the X chromosome and the symptoms include moderate to severe mental retardation (overall IQ 200 copies. The CGG repeats are associated with hypermethylation, chromatin condensation, and subsequent transcriptional silencing of the fmr-1 promoter.

FXS occurs because the mutated fmr-1 gene does not produce enough FMRP, which is needed for normal dendritic spine development. FMRP is a multifunctional mRNA binding protein involved in the transport, localization, and translational regulation of mRNA ligands. The protein has two hnRNP K homology domains and one RGG box as well as nuclear localization and export signals. The RGG box of FMRP mediates interactions with G quartet sequences in mRNA ligands. In neurons, FMRP is located in polysomes and in nontranslating ribonucleoprotein (RNP) particles of dendrites. The RNPs contain the FMRP homologs FXR1 and 2, the guide RNA BC1 and other proteins and mRNAs involved in synaptic plasticity. Hundreds of mRNA ligands have been identified, with many found at synapses and having the potential to influence synapse formation and synaptic plasticity. It has been proposed that FMRP is an “immediate early protein” at the synapse orchestrating synaptic development and plasticity.

We are investigating the translational regulation of synaptic density proteins by FMRP in a mouse model of FXS. In our PLoS paper (2007), we demonstrate that FMRP binds to the coding region of APP mRNA at a guanine-rich region adjacent to a G-quartet–like sequence. Stimulation of cortical synaptoneurosomes or primary neuronal cells with the group 1 metabotropic glutamate receptor (mGluR) agonist DHPG increases APP translation in wild-type but not fmr-1 knockout samples. APP mRNA coimmunoprecipitates with FMRP in resting synaptoneurosomes, but the interaction is lost shortly after DHPG treatment. Soluble Aβ1-40 and Aβ1-42 levels are significantly higher in two strains of fmr-1 knockout mice compared to wild-type controls. These findings incriminate FMRP in translational repression of APP mRNA at the synapse and suggest that group 1 mGluR activation overrides tonic inhibition.

APP mRNA is highly expressed in neurons and dendrites with overexpression implicated in Alzheimer disease (AD). AD is a progressive form of dementia characterized histologically by Aβ plaques, neurofibrillary tangles, and neuronal cell death. Patients suffer memory loss, impaired judgment, cognitive dysfunction, the inability to perform everyday tasks, and behavioral problems. Aβ is processed from the APP parent molecule. The normal physiological function of APP is not well defined, but it is expressed at synapses where it promotes synapse differentiation during development. APP exhibits increased expression during neuronal differentiation with maximal levels at synaptic connection completion. Of note, the role of synaptic dysfunction has received increasing attention as a primary upstream lesion in early AD. Thus, APP facilitates synapse formation in the developing brain, while Aβ accumulation results in synaptic loss and impaired neurotransmission. Our data indicates that postsynaptic FMRP binds to and regulates the translation of APP mRNA through group 1 mGluR activation and suggests a possible link between two neurological disorders, Alzheimer disease (AD) and FXS. Roles for APP in FXS, and FMRP in AD, have not been previously investigated.


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Webinar Citations

  1. Alzheimer Disease—The Fragile X Syndrome Connection

Other Citations

  1. View Presentation

External Citations

  1. PLoS paper
  2. synopsis
  3. Public Library of Science
  4. PC
  5. Mac

Further Reading


  1. . A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9879-84. PubMed.