1. Academic Validation
  2. Neddylation activity modulates the neurodegeneration associated with fragile X associated tremor/ataxia syndrome (FXTAS) through regulating Sima

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

  • Neurobiol Dis. 2020 Sep;143:105013. doi: 10.1016/j.nbd.2020.105013.
Yunting Lin 1 Jin Xue 2 Jing Deng 2 Hua He 2 Shiyu Luo 2 Jia Chen 2 Jia Li 2 Li Yu 2 Juan Zhao 2 Jing Chen 3 Emily G Allen 4 Peng Jin 5 Ranhui Duan 6
Affiliations

Affiliations

  • 1 Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, China; 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.
  • 5 Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA. Electronic address: peng.jin@emory.edu.
  • 6 Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, China; Hunan Key Laboratory of Medical Genetics, Central South University, Changsha 410078, Hunan, China; Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha 410078, Hunan, China. Electronic address: duanranhui@sklmg.edu.cn.
Abstract

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.

Keywords

Chemical screen; Drosophila; FXTAS; HIF1α/Sima; Neddylation.

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