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Human Molecular Genetics, 2000, Vol. 9, No. 1 69-78
© 2000 Oxford University Press

Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado–Joseph disease gene product with an expanded polyglutamine stretch

Toshihiro Yoshizawa+, Yasuaki Yamagishi, Naoteru Koseki, Jun Goto1, Hideaki Yoshida, Futoshi Shibasaki2, Shin’ichi Shoji and Ichiro Kanazawa1

Department of Neurology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan, 1Department of Neurology, University of Tokyo Hospital, Tokyo 113-8655, Japan and 2Department of Molecular Cell Physiology, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan

Machado–Joseph disease (MJD) is an inherited neurodegenerative disorder caused by the expansion of the polyglutamine stretch in the MJD gene-encoded protein, ataxin-3. Using a series of deletion constructs expressing ataxin-3 fragments with expanded polyglutamine stretches, we observed aggregate formation and cell death in cultured BHK-21 cells. The cytotoxic effect of N-terminal-truncated ataxin-3 with the expanded polyglutamine tract was enhanced under serum starvation culture, in which cells were arrested in the G0/G1 phase. Coexpression of p21waf1/cip1/sdi1, a cyclin–Cdk inhibitor that induced cell cycle arrest in the G1 phase, also increased the cell death susceptibility produced by the mutant ataxin-3 fragment in BHK-21 cells. The elevated susceptibility to cell death in the G0/G1 phase was confirmed in nerve growth factor-treated, postmitotic neuronal PC12 cells compared with undifferentiated proliferating PC12 cells. These results strongly suggest that the cellular toxicity of truncated ataxin-3 with an expanded polyglutamine stretch is enhanced by cell cycle arrest in the G0/G1 phase. Mutant ataxin-3 may confer a higher susceptibility to cell death on cells in the G0/G1 phase.

+ To whom correspondence should be addressed. Tel: +81 298 53 3223; Fax: +81 298 53 3224; Email: toshi-yo@md.tsukuba.ac.jp


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