The ataxin-1 interactome reveals direct connection with multiple disrupted nuclear transport pathways

Sunyuan Zhang, Nicholas A. Williamson, Lisa Duvick, Alexander Lee, Harry T. Orr, Austin Korlin-Downs, Praseuth Yang, Yee-Foong Mok, David A. Jans () and Marie A. Bogoyevitch
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Sunyuan Zhang: University of Melbourne
Nicholas A. Williamson: University of Melbourne
Lisa Duvick: University of Minnesota
Alexander Lee: Monash University
Harry T. Orr: University of Minnesota
Austin Korlin-Downs: University of Minnesota
Praseuth Yang: University of Minnesota
Yee-Foong Mok: University of Melbourne
David A. Jans: Monash University
Marie A. Bogoyevitch: University of Melbourne

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-17145-0

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