Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome

Neuron. 2007 Aug 16;55(4):556-64. doi: 10.1016/j.neuron.2007.07.020.


Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently recognized neurodegenerative disorder in fragile X premutation carriers with FMR1 alleles containing 55-200 CGG repeats. Previously, we developed a Drosophila model of FXTAS and demonstrated that transcribed premutation repeats alone are sufficient to cause neurodegeneration, suggesting that rCGG-repeat-binding proteins (RBPs) may be sequestered from their normal function by rCGG binding. Here, we identify Pur alpha and hnRNP A2/B1 as RBPs. We show that Pur alpha and rCGG repeats interact in a sequence-specific fashion that is conserved between mammals and Drosophila. Overexpression of Pur alpha in Drosophila could suppress rCGG-mediated neurodegeneration in a dose-dependent manner. Furthermore, Pur alpha is also present in the inclusions of FXTAS patient brains. These findings support the disease mechanism of FXTAS of rCGG repeat sequestration of specific RBPs, leading to neuronal cell death, and implicate that Pur alpha plays an important role in the pathogenesis of FXTAS.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Eye / pathology
  • Eye / ultrastructure
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / complications*
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HSP70 Heat-Shock Proteins / metabolism
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism
  • Humans
  • Immunoprecipitation / methods
  • Mice
  • Microscopy, Electron, Scanning / methods
  • Nerve Degeneration / genetics*
  • Nerve Degeneration / pathology
  • Nerve Tissue Proteins
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Trinucleotide Repeat Expansion / genetics*


  • DNA-Binding Proteins
  • Drosophila Proteins
  • HSP70 Heat-Shock Proteins
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Nerve Tissue Proteins
  • Pur-alpha protein, Drosophila
  • RNA-Binding Proteins
  • Transcription Factors
  • c-MYC-associated zinc finger protein
  • Fragile X Mental Retardation Protein
  • Green Fluorescent Proteins