TY - JOUR T1 - Polyglutamine-Expanded Ataxin-7 Promotes Non-Cell-Autonomous Purkinje Cell Degeneration and Displays Proteolytic Cleavage in Ataxic Transgenic Mice JF - The Journal of Neuroscience JO - J. Neurosci. SP - 4897 LP - 4905 DO - 10.1523/JNEUROSCI.22-12-04897.2002 VL - 22 IS - 12 AU - Gwenn A. Garden AU - Randell T. Libby AU - Ying-Hui Fu AU - Yoshito Kinoshita AU - Jing Huang AU - Daniel E. Possin AU - Annette C. Smith AU - Refugio A. Martinez AU - Gabriel C. Fine AU - Sara K. Grote AU - Carol B. Ware AU - David D. Einum AU - Richard S. Morrison AU - Louis J. Ptacek AU - Bryce L. Sopher AU - Albert R. La Spada Y1 - 2002/06/15 UR - http://www.jneurosci.org/content/22/12/4897.abstract N2 - 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. ER -