Abstract
Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative disorders caused by an expansion of a polyglutamine tract1,2. It is characterized by ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells1. To understand the pathogenesis of SCA1, we examined the subcellular localization of wild-type human ataxin-1 (the protein encoded by the SCA1 gene) and mutant ataxin-1 in the Purkinje cells of transgenic mice3. We found that ataxin-1 localizes to the nuclei of cerebellar Purkinje cells. Normal ataxin-1 localizes to several nuclear structures ∼0.5 µm across, whereas the expanded ataxin-1 localizes to a single ∼2-µm structure, before the onset of ataxia. Mutant ataxin-1 localizes to a single nuclear structure in affected neurons of SCA1 patients. Similarly, COS-1 cells transfected with wild-type or mutant ataxin-1 show a similar pattern of nuclear localization; with expanded ataxin-1 occurring in larger structures that are fewer in number than those of normal ataxin-1. Colocalization studies show that mutant ataxin-1 causes a specific redistribution of the nuclear matrix-associated domain containing promyelocytic leukaemia protein4,5,6,7. Nuclear matrix preparations demonstrate that ataxin-1 associates with the nuclear matrix in Purkinje and COS cells. We therefore propose that a critical aspect of SCA1 pathogenesis involves the disruption of a nuclear matrix-associated domain.
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Acknowledgements
We thank V. Bardwell for assistance with the BCL-6 transfections; E. N. Burright for assistance with SCA1 transgenic mice; D. Saxon for assistance with tissue sectioning and staining; G.Sedgewick for assistance with confocal microscopy and image processing; D. Armstrong for assistance in analysis of SCA1 human tissue; T. Maniatis for the anti-SC35 antibody; A. Dejean for the anti-PML polysera; R. Van Driel for the anti-PML monoclonal antibody 5E10; and E. K. Chan for the anti-p80-coilin polysera. This work was supported by grants from the National Institute of Neurological Disorders and Stroke of the NIH to H.T.O. and H.Y.Z. H.Y.Z. is a Howard Hughes Medical Institute investigator.
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Skinner, P., Koshy, B., Cummings, C. et al. Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 389, 971–974 (1997). https://doi.org/10.1038/40153
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DOI: https://doi.org/10.1038/40153
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