The pathophysiology of fragile X (and what it teaches us about synapses)

Annu Rev Neurosci. 2012;35:417-43. doi: 10.1146/annurev-neuro-060909-153138. Epub 2012 Apr 5.

Abstract

Fragile X is the most common known inherited cause of intellectual disability and autism, and it typically results from transcriptional silencing of FMR1 and loss of the encoded protein, FMRP (fragile X mental retardation protein). FMRP is an mRNA-binding protein that functions at many synapses to inhibit local translation stimulated by metabotropic glutamate receptors (mGluRs) 1 and 5. Recent studies on the biology of FMRP and the signaling pathways downstream of mGluR1/5 have yielded deeper insight into how synaptic protein synthesis and plasticity are regulated by experience. This new knowledge has also suggested ways that altered signaling and synaptic function can be corrected in fragile X, and human clinical trials based on this information are under way.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / physiopathology*
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / physiology*
  • Fragile X Syndrome / metabolism
  • Fragile X Syndrome / physiopathology*
  • Gene Expression Regulation / physiology
  • Humans
  • Models, Biological
  • Nerve Tissue Proteins / biosynthesis
  • Neuronal Plasticity / physiology
  • Protein Biosynthesis / physiology
  • RNA / metabolism
  • Receptors, Metabotropic Glutamate / metabolism
  • Signal Transduction / physiology
  • Synapses / metabolism
  • Synapses / physiology*

Substances

  • FMR1 protein, human
  • Nerve Tissue Proteins
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • Fragile X Mental Retardation Protein
  • RNA