2. Academic Validation
  3. 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: [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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