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Updated: May 25, 2026
In Vivo Forward Genetic Screen to Identify Novel Neuroprotective Genes in Drosophila melanogaster
Published on: July 11, 2019
Chemical screen reveals small molecules suppressing fragile X premutation rCGG repeat-mediated neurodegeneration in
Abrar Qurashi1, Huijie Liu, Laurie Ray
1Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Abstract:
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.
Insights
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder. This study identified phospholipase A(2) (PLA(2)) inhibitors as potential treatments for FXTAS by mitigating toxic CGG repeat effects in a Drosophila model.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder affecting fragile X premutation carriers.
- Elongated non-coding CGG repeats in the FMR1 gene are identified as the cause of FXTAS.
- Drosophila melanogaster serves as a valuable model for studying FXTAS pathogenesis.
Purpose of the Study:
- To identify small molecules that can ameliorate the toxic effects of CGG repeats in a Drosophila model of FXTAS.
- To investigate the role of phospholipase A(2) (PLA(2)) in FXTAS pathogenesis and explore its potential as a therapeutic target.
Main Methods:
- Utilized a Drosophila model of FXTAS for chemical and genetic screens.
- Conducted a chemical screen to identify small molecules mitigating CGG repeat toxicity.
- Performed a genetic screen to identify Drosophila genes modulating CGG repeat-mediated neuronal toxicity.
Main Results:
- Several phospholipase A(2) (PLA(2)) inhibitors were identified as effective in ameliorating toxic effects of CGG repeats.
- Specific inhibition of PLA(2) activity mitigated neuronal deficits, including lethality and locomotion impairments, in the Drosophila model.
- A Drosophila PLA(2) ortholog was identified that modulates CGG repeat-mediated neuronal toxicity.
Conclusions:
- Drosophila models are effective for unbiased small molecule screens in neurodegenerative disease research.
- Phospholipase A(2) (PLA(2)) represents a potential therapeutic target for treating Fragile X-associated tremor/ataxia syndrome (FXTAS).
