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Human Molecular Genetics, 2001, Vol. 10, No. 16 1679-1692
© 2001 Oxford University Press

SCA7 mouse models show selective stabilization of mutant ataxin-7 and similar cellular responses in different neuronal cell types

Gaël Yvert, Katrin S. Lindenberg1, Didier Devys, Dominique Helmlinger, G. Bernhard Landwehrmeyer1 and Jean-Louis Mandel+

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, B.P.163, 67404 Illkirch cedex, CU de Strasbourg, France and 1Department of Neurology, University of Ulm, 89075 Ulm, Germany

Accumulation of expanded polyglutamine proteins and selective pattern of neuronal loss are hallmarks of at least eight neurodegenerative disorders, including spinocerebellar ataxia type 7 (SCA7). We previously described SCA7 mice displaying neurodegeneration with progressive ataxin-7 accumulation in two cell types affected in the human pathology. We describe here a new transgenic model with a more widespread expression of mutant ataxin-7, including neuronal cell types unaffected in SCA7. In these mice a similar handling of mutant ataxin-7, including a cytoplasm to nucleus translocation and accumulation of N-terminal fragments, was observed in all neuronal populations studied. An extensive screen for chaperones, proteasomal subunits and transcription factors sequestered in nuclear inclusions (NIs) disclosed no pattern unique to neurons undergoing degeneration in SCA7. In particular, we found that the mouse TAFII30 subunit of the TFIID initiation complex is markedly accumulated in NIs, even though this protein does not contain a polyglutamine stretch. A striking discrepancy between mRNA and ataxin-7 levels in transgenic mice expressing the wild-type protein but not in those expressing the mutant one, indicates a selective stabilization of mutant ataxin-7, both in this model and the P7E/N model described previously. These mice therefore provide in vivo evidence that the polyglutamine expansion mutation can stabilize its target protein.

+ To whom correspondence should be addressed. Tel: +33 3 88 65 32 44; Fax: +33 3 88 65 32 46; Email: mandeljl@igbmc.u-strasbg.frPresent address: Gaël Yvert, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA


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