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Human Molecular Genetics, 1999, Vol. 8, No. 7 1169-1176
© 1999 Oxford University Press

Article

High level expression of expanded full-length ataxin-3 in vitro causes cell death and formation of intranuclear inclusions in neuronal cells

Bernd O. Everta, Ullrich Wüllner1, Jörg B. Schulz, Michael Weller, Peter Groscurth2, Yvon Trottier3, Alexis Brice4 and Thomas Klockgether1

Department of Neurology, University of Tübingen, 72076 Tübingen, Germany, 1Department of Neurology, University of Bonn, 53105 Bonn, Germany, 2Department of Anatomy, University of Zürich, 8057 Zürich, Switzerland, 3Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch Cédex, France and 4Hôpital de la Salpêtrière, 75651 Paris Cédex 13, France

Spinocerebellar ataxia type 3 (SCA3) is caused by a CAG/polyglutamine repeat expansion in the SCA3 gene. To analyse the pathogenic mechanisms in SCA3, we have generated ataxin-3-expressing rat mesencephalic CSM14.1 cells. In these cells, a post-mitotic neuronal phenotype is induced by temperature shift. The isolated stable cell lines provided high level expression of non-expanded (Q23) or expanded (Q70) human full-length ataxin-3. CSM14.1 cells expressing the expanded full-length ataxin-3 developed nuclear inclusion bodies, strong indentations of the nuclear envelope and cytoplasmic vacuolation. These ultrastructural alterations were present prior to a significantly decreased viability of neuronally differentiated cells expressing expanded ataxin-3. The observed spontaneous cell death did not correlate with formation of intranuclear inclusions and was not apoptotic by ultrastructural analysis. No increased susceptibility to staurosporine-induced apoptosis was found for the expanded or non-expanded ataxin-3-expressing cell lines. These data show that high level expression of expanded full-length ataxin-3 in a neuron-like cell line generates ultrastructural alter­ations of SCA3 pathogenesis and results in increased spontaneous non-apoptotic cell death.

a To whom correspondence should be addressed. Tel: +49 228 287 6130; Fax: +49 228 287 5024; Email: b.evert{at}uni-bonn.de


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