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

Autor: Zhang S; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, 3010, Australia., Williamson NA; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia., Duvick L; Institute of Translational Neuroscience, and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA., Lee A; Nuclear Signalling Lab., Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia., Orr HT; Institute of Translational Neuroscience, and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA., Korlin-Downs A; Institute of Translational Neuroscience, and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA., Yang P; Institute of Translational Neuroscience, and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA., Mok YF; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia., Jans DA; Nuclear Signalling Lab., Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia. david.jans@monash.edu., Bogoyevitch MA; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2020 Jul 03; Vol. 11 (1), pp. 3343. Date of Electronic Publication: 2020 Jul 03.
DOI: 10.1038/s41467-020-17145-0
Abstrakt: 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.
Databáze: MEDLINE
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