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Human Molecular Genetics, 2000, Vol. 9, No. 17 2491-2506
© 2000 Oxford University Press

Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice

Gaël Yvert1, Katrin S. Lindenberg2,3, Serge Picaud4, G. Bernhard Landwehrmeyer2,3, José-Alain Sahel4 and Jean-Louis Mandel1,+

1Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 163, 67404 Illkirch cedex, CU de Strasbourg, France, 2Department of Neurology, Albert Ludwigs-University, 79106 Freiburg, Germany, 3Department of Neurology, University of Ulm, 89075 Ulm, Germany and 4Laboratoire de physiopathologie de la rétine, INSERM EMI-99–18, Université Louis Pasteur, BP 426, 67091 Strasbourg cedex, France

Among the eight progressive neurodegenerative diseases caused by polyglutamine expansions, spinocerebellar ataxia type 7 (SCA7) is the only one to display degeneration in both brain and retina. We show here that mice overexpressing full-length mutant ataxin-7[Q90] either in Purkinje cells or in rod photoreceptors have deficiencies in motor coordination and vision, respectively. In both models, although with different time courses, an N-terminal fragment of mutant ataxin-7 accumulates into ubiquitinated nuclear inclusions that recruit a distinct set of chaperone/proteasome subunits. A severe degeneration is caused by overexpression of ataxin-7[Q90] in rods, whereas a similar overexpression of normal ataxin-7[Q10] has no obvious effect. The degenerative process is not limited to photoreceptors, showing secondary alterations of post-synaptic neurons. These findings suggest that proteolytic cleavage of mutant ataxin-7 and trans-neuronal responses are implicated in the pathogenesis of SCA7.

+ To whom correspondence should be addressed. Tel: + 33 3 88 65 34 12; Fax: + 33 3 88 65 34 42; Email: mandeljl@igbmc.u-strasbg.fr


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