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, Marie A. Bogoyevitch

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number3343
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

Bibliographical note

Funding Information:
This work was funded by a grant (1121907) to M.A.B. and D.A.J. from the Australian National Health and Medical Research Council (NHMRC), and an NIH/NINDS grant to H.T.O. (NS022920-30). S.Z. also acknowledges the scholarship support by the University of Melbourne (Melbourne International Research Scholarship). The mycBioID vector (pcDNA3.1 mycBioID) was a gift from K. Roux (addgene plasmid # 35700), the BiFC vectors were a gift from C.-D. Hu (addgene plasmids #22011, #22013, #22014, # 27097, #27098), and the GFP-ataxin-1[85Q] and GFP-ataxin-1[30Q] plasmids were provided by D.M. Hatters (University of Melbourne). We acknowledge access to the following facilities at the University of Melbourne: the Bio21 Institute Mass Spectrometry and Proteomics Facility, the Macromolecular Interactions Facility, Melbourne Brain Centre (MBC) flow cytometry facility, and the Biological Optical Microscopy Platform. We also acknowledge access to the Monash Micro Imaging Facility at Monash University, Clayton.

Publisher Copyright:
© 2020, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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