Neddylation activity modulates the neurodegeneration associated with fragile X associated tremor/ataxia syndrome (FXTAS) through regulating Sima

Neurobiology of Disease

卷:143

Jin Xue¹  Jia Li²  Li Yu²  Jing Chen²  Jia Chen²  Shiyu Luo²  Yunting Lin²  Hua He²  Juan Zhao²  Jing Deng²  Emily G. Allen³  Ranhui Duan⁴  Peng Jin⁴ 

[1] Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China;

[2] Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, China;

[3] Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA;

[4] Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA;

关键词: FXTAS;    Drosophila;    Chemical screen;    Neddylation;    HIF1α/Sima;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown