Chemical screen reveals small molecules suppressing fragile X premutation rCGG repeat-mediated neurodegeneration in Drosophila

Hum Mol Genet. 2012 May 1;21(9):2068-75. doi: 10.1093/hmg/dds024. Epub 2012 Feb 1.


Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder recognized in fragile X premutation carriers. Using Drosophila, we previously identified elongated non-coding CGG repeats in FMR1 allele as the pathogenic cause of FXTAS. Here, we use this same FXTAS Drosophila model to conduct a chemical screen that reveals small molecules that can ameliorate the toxic effects of fragile X premutation ribo-CGG (rCGG) repeats, among them several known phospholipase A(2) (PLA(2)) inhibitors. We show that specific inhibition of PLA(2) activity could mitigate the neuronal deficits caused by fragile X premutation rCGG repeats, including lethality and locomotion deficits. Furthermore, through a genetic screen, we identified a PLA(2) Drosophila ortholog that specifically modulates rCGG repeat-mediated neuronal toxicity. Our results demonstrate the utility of Drosophila models for unbiased small molecule screens and point to PLA(2) as a possible therapeutic target to treat FXTAS.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Drosophila / drug effects
  • Drosophila / genetics
  • Drosophila / physiology
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / genetics*
  • Fragile X Syndrome / physiopathology
  • Genetic Testing
  • Humans
  • Male
  • Mice
  • Mutation
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / genetics*
  • Nerve Degeneration / physiopathology
  • Phospholipase A2 Inhibitors
  • Trinucleotide Repeat Expansion


  • Enzyme Inhibitors
  • FMR1 protein, human
  • Phospholipase A2 Inhibitors
  • Fragile X Mental Retardation Protein