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The Journal of Neuroscience, July 11, 2007, 27(28):7418-7428; doi:10.1523/JNEUROSCI.4540-06.2007

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Cellular/Molecular
Nuclear Localization of Ataxin-3 Is Required for the Manifestation of Symptoms in SCA3: In Vivo Evidence

Ulrike Bichelmeier,¹ Thorsten Schmidt,^1 * Jeannette Hübener,^1 * Jana Boy,¹ Lukas Rüttiger,² Karina Häbig,¹ Sven Poths,¹ Michael Bonin,¹ Marlies Knipper,² Werner J. Schmidt,³  Johannes Wilbertz,⁵ Hartwig Wolburg,⁴ Franco Laccone,⁶ and Olaf Riess¹

Departments of ¹Medical Genetics and ²Otorhinolaryngology, ³Zoological Institute, Neuropharmacology, and ⁴Institute for Pathology, University of Tübingen, D-72076 Tübingen, Germany, ⁵Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden, and ⁶Department of Medical Genetics, University of Vienna, A-1090 Vienna, Austria

Correspondence should be addressed to Olaf Riess, Department of Medical Genetics, University of Tübingen, Calwerstrasse 7, D-72076 Tübingen, Germany. Email: Olaf.Riess{at}med.uni-tuebingen.de

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited neurodegenerative disorder caused by the expansion of a CAG repeat in the MJD1 gene resulting in an expanded polyglutamine repeat in the ataxin-3 protein. To study the course of the disease, we generated transgenic mice for SCA3 using full-length ataxin-3 constructs containing 15, 70, or 148 CAG repeats, respectively. Control mice (15 CAGs) were phenotypically normal and had no neuropathological findings. However, mice transgenic for ataxin-3 with expanded polyglutamine repeats were severely affected by a strong neurological phenotype with tremor, behavioral deficits, strongly reduced motor and exploratory activity, a hunchback, and premature death at 3 to 6 months of age. Neuropathological examination by immunohistochemical staining revealed ubiquitin- and ataxin-3-positive intranuclear inclusion bodies in a multitude of neurons. Directing ataxin-3 with 148 CAGs to the nucleus revealed an even more pronounced phenotype with more inclusions and earlier death, whereas mice transgenic with the same construct but attached to a nuclear export signal developed a milder phenotype with less inclusions. These studies indicate that nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3 in vivo.

Key words: neurodegenerative diseases; polyglutamine diseases; spinocerebellar ataxia type 3 (SCA3); Machado–Joseph disease (MJD); mouse model; nuclear localization

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Received Nov. 10, 2005; revised June 1, 2007; accepted June 4, 2007.

Correspondence should be addressed to Olaf Riess, Department of Medical Genetics, University of Tübingen, Calwerstrasse 7, D-72076 Tübingen, Germany. Email: Olaf.Riess{at}med.uni-tuebingen.de

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