Lin, Y., Xue, J., Deng, J., He, H., Luo, S., Chen, J., Li, J., Yu, L., Zhao, J., Chen, J., Allen, E.G., Jin, P., Duan, R. (2020). Neddylation activity modulates the neurodegeneration associated with fragile X associated tremor/ataxia syndrome (FXTAS) through regulating Sima.  Neurobiol. Disease 143(): 105013.

FBrf0246305

Research paper

Fragile X associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expansion of CGG repeats in the 5' UTR of the fragile X mental retardation 1 (FMR1) gene. Using the well-established FXTAS Drosophila model, we performed a high-throughput chemical screen using 3200 small molecules. NSC363998 was identified to suppress the neurodegeneration caused by riboCGG (rCGG) repeats. Three predicted targets of a NSC363998 derivative are isopeptidases in the neddylation pathway and could modulate the neurotoxicity caused by the rCGG repeats. Decreasing levels of neddylation resulted in enhancing neurodegeneration phenotypes, while up-regulation could rescue the phenotypes. Furthermore, known neddylation substrates, Cul3 and Vhl, and their downstream target, Sima, were found to modulate rCGG90-dependent neurotoxicity. Our results suggest that altered neddylation activity can modulate the rCGG repeat-mediated toxicity by regulating Sima protein levels, which could serve as a potential therapeutic target for FXTAS.