Abstract
Instability of CAG DNA trinucleotide repeats is the mutational mechanism for several neurodegenerative diseases resulting in the expansion of a polyglutamine (polyQ) tract. Proteins with long polyQ tracts have an increased tendency to aggregate, often as truncated fragments forming ubiquitinated intranuclear inclusion bodies. We examined whether similar features define spinocerebellar ataxia type 2 (SCA2) pathogenesis using cultured cells, human brains and transgenic mouse lines. In SCA2 brains, we found cytoplasmic, but not nuclear, microaggregates. Mice expressing ataxin-2 with Q58 showed progressive functional deficits accompanied by loss of the Purkinje cell dendritic 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.
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Acknowledgements
We thank A. Koeppen and M. Del Bigio for tissue samples from SCA2 patients; H. Orr for the pZ03-β-Gal expression vector with the Pcp2 promoter; C. Readhead and M. Schibler for assistance with transgenic mouse lines and confocal microscopy, respectively; T. Ho, A. Schlesinger and M. Dy for technical support; and D. Scoles and T.-R. Kiehl for critically reading the manuscript. This work was supported by the Carmen and Louis Warschaw Endowment for Neurology, F.R.I.E.N.D.s of Neurology, the National Ataxia Foundation, grant RO1-NS33123 (SMP) and a Long Term Disabled Scientist Supplement (DPH) from the National Institutes of Health.
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Huynh, D., Figueroa, K., Hoang, N. et al. Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human. Nat Genet 26, 44–50 (2000). https://doi.org/10.1038/79162
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DOI: https://doi.org/10.1038/79162
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