Chemical screen reveals small molecules suppressing fragile X premutation rCGG repeat-mediated neurodegeneration in Drosophila.
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.
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Abrar
A
Qurashi
Huijie
H
Liu
Laurie
L
Ray
David L
DL
Nelson
Ranhui
R
Duan
Peng
P
Jin
D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004330:Drosophila / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D005820:Genetic Testing; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D064801:Phospholipase A2 Inhibitors; D019680:Trinucleotide Repeat Expansion
D004791:Enzyme Inhibitors; D051860:Fragile X Messenger Ribonucleoprotein 1; D064801:Phospholipase A2 Inhibitors; C497683:FMR1 protein, human