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.
Highlights
The expanded polyglutamine tract form of ataxin-1 drives disease progression in spinocerebellar ataxia type 1 (SCA1)
Our assessment of ataxin-1 aggregate formation by analytical ultracentrifugation analyses of lysates prepared from these cells, showed increased aggregates for both GFP-ataxin-1 [85Q] and the non-pathogenic GFP-ataxin-1[85Q] S766A (Supplementary Fig. 1d), emphasising that aggregation state and visible body size do not always change in parallel as has been reported for the huntingtin protein with an expanded polyQ tract[24,25] and as we have recently observed for polyQ-ataxin-126
Whilst GFP remains broadly distributed throughout the cell, GFP-ataxin-1[85Q] forms distinctive nuclear bodies that have been reported across a range of cell types[15,20]
Summary
The expanded polyglutamine (polyQ) tract form of ataxin-1 drives disease progression in spinocerebellar ataxia type 1 (SCA1). We observed prominent nuclear localisation of GFP-NLS-βgal under both control and arsenite stress conditions, as expected, but we noted increased cytoplasmic levels of this protein under both conditions in the presence of ataxin-1
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