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Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human

Nature Genetics volume 26, pages 44–50 (2000)Cite this article

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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Figure 1: Schematic map of ataxin-2.
Figure 2: Expression of ataxin-2.
Figure 3: Immunohistochemical staining of cerebellar sections from a normal individual (a–c) and an SCA2 patient with 58 CAG repeats (d–f).
Figure 4: Expression of the human ataxin-2 transgene in mice as seen by RT–PCR and western-blot analyses.
Figure 7: Expression and localization of ataxin-2 in Purkinje cells.
Figure 5: Progressive functional loss in lines Q58-5B, Q58-11 and Q58-19.
Figure 6: Calbindin-28K labelling of cerebella of heterozygous Q58-5B (a), Q58-11 (b) and Q58-19 (c) animals at 27 weeks, and wild-type and homozygous Q58-11 mice at 4 weeks (d,g), 7 weeks (e,h) and 14 weeks (f,i) .

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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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  1. Rose Moss Laboratory for Parkinson's and Neurodegenerative Diseases, CSMC Burns and Allen Research Institute, and Division of Neurology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California, USA

    Duong P. Huynh, Karla Figueroa, Nam Hoang & Stefan-M. Pulst

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Correspondence to Stefan-M. Pulst.

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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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