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The ataxin-1 interactome reveals direct connection with multiple disrupted nuclear transport pathways.
Nature Communications ( IF 14.7 ) Pub Date : 2020-07-03 , DOI: 10.1038/s41467-020-17145-0
Sunyuan Zhang 1 , Nicholas A Williamson 2 , Lisa Duvick 3 , Alexander Lee 4 , Harry T Orr 3 , Austin Korlin-Downs 3 , Praseuth Yang 3 , Yee-Foong Mok 2 , David A Jans 4 , Marie A Bogoyevitch 1
Affiliation  

The expanded polyglutamine (polyQ) tract form of ataxin-1 drives disease progression in spinocerebellar ataxia type 1 (SCA1). Although known to form distinctive intranuclear bodies, the cellular pathways and processes that polyQ-ataxin-1 influences remain poorly understood. Here we identify the direct and proximal partners constituting the interactome of ataxin-1[85Q] in Neuro-2a cells, pathways analyses indicating a significant enrichment of essential nuclear transporters, pointing to disruptions in nuclear transport processes in the presence of elevated levels of ataxin-1. Our direct assessments of nuclear transporters and their cargoes confirm these observations, revealing disrupted trafficking often with relocalisation of transporters and/or cargoes to ataxin-1[85Q] nuclear bodies. Analogous changes in importin-β1, nucleoporin 98 and nucleoporin 62 nuclear rim staining are observed in Purkinje cells of ATXN1[82Q] mice. The results highlight a disruption of multiple essential nuclear protein trafficking pathways by polyQ-ataxin-1, a key contribution to furthering understanding of pathogenic mechanisms initiated by polyQ tract proteins.



中文翻译:


ataxin-1 相互作用组揭示了与多个中断的核运输途径的直接联系。



ataxin-1 的扩展多聚谷氨酰胺 (polyQ) 束形式可驱动 1 型脊髓小脑共济失调 (SCA1) 的疾病进展。尽管已知可以形成独特的核内体,但 polyQ-ataxin-1 影响的细胞途径和过程仍然知之甚少。在这里,我们确定了 Neuro-2a 细胞中构成 ataxin-1[85Q] 相互作用组的直接和近端伙伴,通路分析表明必需核转运蛋白显着富集,表明在 ataxin 水平升高的情况下核转运过程会受到破坏-1。我们对核转运蛋白及其货物的直接评估证实了这些观察结果,揭示了通常随着转运蛋白和/或货物重新定位到ataxin-1[85Q]核体而导致的贩运中断。在ATXN1 [82Q] 小鼠的浦肯野细胞中观察到输入蛋白-β1、核孔蛋白 98 和核孔蛋白 62 核边缘染色的类似变化。结果强调了polyQ-ataxin-1对多种重要核蛋白运输途径的破坏,这对进一步了解polyQ束蛋白引发的致病机制做出了关键贡献。

更新日期:2020-07-03
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