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

• 影响指数: 7.046
• 发表时间: 09 2020
• 来源期刊: Neurobiol Dis
• DOI: 10.1016/j.nbd.2020.105013
• PMID: 32653676
• 文章类型: Journal Article
• 中科院分区: Q1
• 方向: 生物
• 作者列表: Lin Y,Xue J,Deng J,He H,Luo S,Chen J,Li J,Yu L,Zhao J,Chen J,Allen EG,Jin P,Duan R

关键词: Chemical screen; Drosophila; FXTAS; HIF1α/Sima; Neddylation

Mesh: Animals; Ataxia / metabolism pathology; Drosophila; Drosophila Proteins / biosynthesis; Fragile X Syndrome / metabolism pathology; Gene Expression Regulation / physiology; Humans; Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis; NEDD8 Protein; Nerve Degeneration / metabolism pathology; Neuroprotective Agents / pharmacology; Protein Processing, Post-Translational / drug effects physiology; Tremor / metabolism pathology; Trinucleotide Repeat Expansion

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.