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
  • 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: [email protected].
  • 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: [email protected].
PMID: 32653676 DOI: 10.1016/j.nbd.2020.105013
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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