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Human Molecular Genetics, 2001, Vol. 10, No. 22 2569-2579
© 2001 Oxford University Press

Similarities between spinocerebellar ataxia type 7 (SCA7) cell models and human brain: proteins recruited in inclusions and activation of caspase-3

C. Zander1,2, J. Takahashi3,8, K. H. El Hachimi4, H. Fujigasaki1, V. Albanese5, A. S. Lebre1, G. Stevanin1, C. Duyckaerts3 and A. Brice1,6,7,+

1INSERM U289, Hôpital de la Salpêtrière, 47 boulevard de l’Hôpital, 75651 Paris, Cedex 13, France, 2Neurogenetics Unit, Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden, 3Laboratoire de Neuropathologie Escourolle, 4INSERM U106 and Ecole Pratique des Hautes Etudes, 5LGN, Bâtiment CERVI, 6Féderation de Neurologie and 7Département de Génétique, Cytogénétique et Embryologie, Hôpital de la Salpêtrière, 75651 Paris, Cedex 13, France, 8Division of Neuropathology, The Jikei University School of Medicine, Tokyo, Japan

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant polyglutamine disorder presenting with progressive cerebellar ataxia and blindness. The molecular mechanisms underlying the selective neuronal death typical of SCA7 are unknown. We have established SCA7 cell culture models in HEK293 and SH-SY5Y cells, in order to analyse the effects of overexpression of the mutant ataxin-7 protein. The cells readily formed anti-ataxin-7 positive, fibrillar inclusions and small, nuclear electron dense structures. We have compared the inclusions in cells expressing mutant ataxin-7 and in human SCA7 brain tissue. There were consistent signs of ongoing abnormal protein folding, including the recruitment of heat-shock proteins and proteasome subunits. Occasionally, sequestered transcription factors were found. Activated caspase-3 was recruited into the inclusions in both the cell models and human SCA7 brain and its expression was upregulated in cortical neurones, suggesting that it may play a role in the disease process. Finally, on the ultrastructural level, there were signs of autophagy and nuclear indentations, indicative of a major stress response in cells expressing mutant ataxin-7.

+ To whom correspondence should be addressed. Tel: +33 1 42 16 21 82; Fax: +33 1 44 24 36 58; Email: brice@ccr.jussieu.frPresent address:V. Albanese, University of Stanford, Stanford, CA 94305-5020, USA


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