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The Journal of Neuroscience, June 15, 2002, 22(12):4897-4905

Polyglutamine-Expanded Ataxin-7 Promotes Non-Cell-Autonomous Purkinje Cell Degeneration and Displays Proteolytic Cleavage in Ataxic Transgenic Mice

Gwenn A. Garden¹, Randell T. Libby², Ying-Hui Fu⁷, Yoshito Kinoshita³, Jing Huang⁴, Daniel E. Possin⁴, Annette C. Smith², Refugio A. Martinez², Gabriel C. Fine¹, Sara K. Grote^{1, 2}, Carol B. Ware⁵, David D. Einum⁸, Richard S. Morrison³, Louis J. Ptacek^{8, 9}, Bryce L. Sopher², and Albert R. La Spada^{1, 2, 6}

Departments of ¹ Neurology, ² Laboratory Medicine, ³ Neurological Surgery, ⁴ Ophthalmology, ⁵ Comparative Medicine, and ⁶ Medicine (Division of Medical Genetics), University of Washington Medical Center, Seattle, Washington 98195-7110, Departments of ⁷ Neurobiology and Anatomy and ⁸ Human Genetics, and ⁹ Howard Hughes Medical Institute, University of Utah, Salt Lake City, Utah 84112

Spinocerebellar ataxia (SCA) type 7 is an inherited neurodegenerative disorder caused by expansion of a polyglutamine tract within the ataxin-7 protein. To determine the molecular basis of polyglutamine neurotoxicity in this and other related disorders, we produced SCA7 transgenic mice that express ataxin-7 with 24 or 92 glutamines in all neurons of the CNS, except for Purkinje cells. Transgenic mice expressing ataxin-7 with 92 glutamines (92Q) developed a dramatic neurological phenotype presenting as a gait ataxia and culminating in premature death. Despite the absence of expression of polyglutamine-expanded ataxin-7 in Purkinje cells, we documented severe Purkinje cell degeneration in 92Q SCA7 transgenic mice. We also detected an N-terminal truncation fragment of ataxin-7 in transgenic mice and in SCA7 patient material with both anti-ataxin-7 and anti-polyglutamine specific antibodies. The appearance of truncated ataxin-7 in nuclear aggregates correlates with the onset of a disease phenotype in the SCA7 mice, suggesting that nuclear localization and proteolytic cleavage may be important features of SCA7 pathogenesis. The non-cell-autonomous nature of the Purkinje cell degeneration in our SCA7 mouse model indicates that polyglutamine-induced dysfunction in adjacent or connecting cell types contributes to the neurodegeneration.

Key words: polyglutamine; ataxin-7; neurodegeneration; Purkinje cell; non-cell autonomous; truncation; proteolytic cleavage

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22124897-09$05.00/0

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