Journal Article

High Level Expression of Expanded Full-length Ataxin-3 <i>In Vitro</i> Causes Cell Death and Formation of Intranuclear Inclusions in Neuronal Cells

Bernd O. Evert, Ullrich Wüllner, Jörg B. Schulz, Michael Weller, Peter Groscurth, Yvon Trottier, Alexis Brice and Thomas Klockgether

in Human Molecular Genetics

Volume 8, issue 7, pages 1169-1176
Published in print July 1999 | ISSN: 0964-6906
Published online July 1999 | e-ISSN: 1460-2083 | DOI:
High Level Expression of Expanded Full-length Ataxin-3 In Vitro Causes Cell Death and Formation of Intranuclear Inclusions in Neuronal Cells

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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.

Journal Article.  6181 words.  Illustrated.

Subjects: Genetics and Genomics

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