Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures.

Abstract

Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative disorders caused by an expansion of a polyglutamine tract. It is characterized by ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells. 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 mice. We found that ataxin-1 localizes to the nuclei of cerebellar Purkinje cells. Normal ataxin-1 localizes to several nuclear structures approximately 0.5 microm across, whereas the expanded ataxin-1 localizes to a single approximately 2-microm 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 protein. 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.

• Authors: P J Skinner, B T Koshy, C J Cummings, I A Klement, K Helin, A Servadio, H Y Zoghbi, H T Orr
• Journal: Nature (Nature) Vol. 389 Issue 6654 Pg. 971-4 (Oct 30 1997) ISSN: 0028-0836 [Print] England
• PMID: 9353120 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATXN1 protein, human
• Ataxin-1
• Ataxins
• Atxn1 protein, mouse
• Nerve Tissue Proteins
• Nuclear Proteins
• Glutamine

Topics

• Animals
• Ataxin-1
• Ataxins
• Brain (metabolism, pathology)
• COS Cells
• Glutamine (chemistry, physiology)
• Humans
• Immunohistochemistry
• Mice
• Mice, Transgenic
• Mutation
• Nerve Tissue Proteins (chemistry, genetics, physiology)
• Nuclear Matrix (pathology)
• Nuclear Proteins (chemistry, genetics, physiology)
• Purkinje Cells (metabolism, pathology)
• Spinocerebellar Degenerations (etiology, genetics, pathology)