Journal Article

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

Abrar Qurashi, Huijie Liu, Laurie Ray, David L. Nelson, Ranhui Duan and Peng Jin

in Human Molecular Genetics

Volume 21, issue 9, pages 2068-2075
Published in print May 2012 | ISSN: 0964-6906
Published online February 2012 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/dds024
Chemical screen reveals small molecules suppressing fragile X premutation rCGG repeat-mediated neurodegeneration in Drosophila

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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 A2 (PLA2) inhibitors. We show that specific inhibition of PLA2 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 PLA2 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 PLA2 as a possible therapeutic target to treat FXTAS.

Journal Article.  4928 words.  Illustrated.

Subjects: Genetics and Genomics

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