Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures.
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.
Skinner
P J
PJ
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA.
Koshy
B T
BT
Cummings
C J
CJ
Klement
I A
IA
Helin
K
K
Servadio
A
A
Zoghbi
H Y
HY
Orr
H T
HT
D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D005973:Glutamine / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015530:Nuclear Matrix / Q000473:pathology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D013132:Spinocerebellar Degenerations / Q000209:etiology / Q000235:genetics / Q000473:pathology*
C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D005973:Glutamine