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Neddylation activity modulates the neurodegeneration associated with fragile X associated tremor/ataxia syndrome (FXTAS) through regulating Sima.
Neurobiol Dis. 2020 Sep; 143:105013.ND

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.

Authors+Show Affiliations

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.Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, China.Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, China.Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, China.Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, China.Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, China.Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, China.Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, China.Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, China.Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA.Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA. Electronic address: peng.jin@emory.edu.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32653676

Citation

Lin, Yunting, et al. "Neddylation Activity Modulates the Neurodegeneration Associated With Fragile X Associated Tremor/ataxia Syndrome (FXTAS) Through Regulating Sima." Neurobiology of Disease, vol. 143, 2020, p. 105013.
Lin Y, Xue J, Deng J, et al. Neddylation activity modulates the neurodegeneration associated with fragile X associated tremor/ataxia syndrome (FXTAS) through regulating Sima. Neurobiol Dis. 2020;143:105013.
Lin, Y., Xue, J., Deng, J., He, H., Luo, S., Chen, J., Li, J., Yu, L., Zhao, J., Chen, J., Allen, E. G., Jin, P., & Duan, R. (2020). Neddylation activity modulates the neurodegeneration associated with fragile X associated tremor/ataxia syndrome (FXTAS) through regulating Sima. Neurobiology of Disease, 143, 105013. https://doi.org/10.1016/j.nbd.2020.105013
Lin Y, et al. Neddylation Activity Modulates the Neurodegeneration Associated With Fragile X Associated Tremor/ataxia Syndrome (FXTAS) Through Regulating Sima. Neurobiol Dis. 2020;143:105013. PubMed PMID: 32653676.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neddylation activity modulates the neurodegeneration associated with fragile X associated tremor/ataxia syndrome (FXTAS) through regulating Sima. AU - Lin,Yunting, AU - Xue,Jin, AU - Deng,Jing, AU - He,Hua, AU - Luo,Shiyu, AU - Chen,Jia, AU - Li,Jia, AU - Yu,Li, AU - Zhao,Juan, AU - Chen,Jing, AU - Allen,Emily G, AU - Jin,Peng, AU - Duan,Ranhui, Y1 - 2020/07/10/ PY - 2019/08/06/received PY - 2020/04/25/revised PY - 2020/07/07/accepted PY - 2020/7/13/pubmed PY - 2020/7/13/medline PY - 2020/7/13/entrez KW - Chemical screen KW - Drosophila KW - FXTAS KW - HIF1α/Sima KW - Neddylation SP - 105013 EP - 105013 JF - Neurobiology of disease JO - Neurobiol. Dis. VL - 143 N2 - 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. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/32653676/Neddylation_activity_modulates_the_neurodegeneration_associated_with_fragile_X_associated_tremor/ataxia_syndrome_(FXTAS)_through_regulating_Sima L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(20)30288-6 DB - PRIME DP - Unbound Medicine ER -
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