Dp. Huynh et al., Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human, NAT GENET, 26(1), 2000, pp. 44-50
Instability of CAG DNA trinucleotide repeats is the mutational mechanism fo
r several neurodegenerative diseases resulting in the expansion of a polygl
utamine (polyQ) tract. Proteins with long polyQ tracts have an increased te
ndency to aggregate, often as truncated fragments forming ubiquitinated int
ranuclear inclusion bodies. We examined whether similar features define spi
nocerebellar ataxia type 2 (SCA2) pathogenesis using cultured cells, human
brains and transgenic mouse lines. In SCA2 brains, we found cytoplasmic, bu
t not nuclear, microaggregates. Mice expressing ataxin-2 with Q58 showed pr
ogressive functional deficits accompanied by loss of the Purkinje cell dend
ritic arbor and finally loss of Purkinje cells. Despite similar functional
deficits and anatomical changes observed in ataxin-1[Q80] transgenic lines,
ataxin-2[Q58] remained cytoplasmic without detectable ubiquitination.