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FMRP mediates mGluR5-dependent translation of amyloid precursor protein

Cara J Westmark1, James S Malter

  • 1Department of Pathology and Laboratory Medicine, Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, Wisconsin, United States of America. westmark@facstaff.wisc.edu

Plos Biology
|February 15, 2007
PubMed

Insights

Fragile X mental retardation protein (FMRP) regulates amyloid precursor protein (APP) translation. Loss of FMRP increases beta-amyloid (Abeta) levels, suggesting a link between fragile X syndrome and Alzheimer disease.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Amyloid precursor protein (APP) is crucial for synapse formation, but its accumulation into beta-amyloid (Abeta) causes synaptic loss in Alzheimer disease.
  • Fragile X mental retardation protein (FMRP) is vital for neuronal development and its absence causes fragile X syndrome.

Purpose of the Study:

  • To investigate the interaction between FMRP and APP mRNA.
  • To determine the role of FMRP in regulating APP translation and Abeta production.
  • To explore a potential link between fragile X syndrome and Alzheimer disease.

Main Methods:

  • Investigated FMRP binding to APP mRNA using biochemical assays.
  • Stimulated neuronal cells and synaptoneurosomes to assess APP translation.
  • Measured Abeta levels in wild-type and FMRP-deficient (fmr-1 knockout) mice.

Main Results:

  • FMRP binds to a specific sequence in APP mRNA.
  • Metabotropic glutamate receptor activation increases APP translation in an FMRP-dependent manner.
  • FMRP deficiency leads to elevated soluble Abeta40 and Abeta42 levels.

Conclusions:

  • Postsynaptic FMRP regulates APP mRNA translation via metabotropic glutamate receptor signaling.
  • Dysregulation of this pathway in fragile X syndrome may contribute to increased Abeta pathology.
  • Findings suggest a molecular link between Alzheimer disease and fragile X syndrome.

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