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

NEUROBIOLOGY OF DISEASE

卷:143

Article

Lin, Yunting^1,2  Xue, Jin¹  Deng, Jing¹  He, Hua¹  Luo, Shiyu¹  Chen, Jia¹  Li, Jia¹  Yu, Li¹  Zhao, Juan¹  Chen, Jing³  Allen, Emily G.⁴  Jin, Peng⁴  Duan, Ranhui^1,5,6 

[1] Cent South Univ, Ctr Med Genet, Sch Life Sci, Changsha 410078, Hunan, Peoples R China

[2] Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Dept Genet & Endocrinol, Guangzhou 510623, Guangdong, Peoples R China

[3] Emory Univ, Sch Med, Winship Canc Inst Emory, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA

[4] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA

[5] Cent South Univ, Hunan Key Lab Med Genet, Changsha 410078, Hunan, Peoples R China

[6] Cent South Univ, Hunan Key Lab Anim Models Human Dis, Changsha 410078, Hunan, Peoples R China

关键词: FXTAS;    Drosophila;    Chemical screen;    Neddylation;    HIF1 alpha/Sima;   

DOI  :  10.1016/j.nbd.2020.105013

来源: Elsevier

【 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 rCGG(90)-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.