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J. Biol. Chem., Vol. 281, Issue 5, 2730-2739, February 3, 2006

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Ataxin-7 Can Export from the Nucleus via a Conserved Exportin-dependent Signal^*

Jillian Taylor, Sara K. Grote, Jianrun Xia, Mark Vandelft, Joanna Graczyk, Lisa M. Ellerby^¶1, Albert R. La Spada², and Ray Truant³

From the Department of Biochemistry and Biomedical Sciences, McMaster University, HSC4H45 Hamilton, Ontario L8N3Z5 Canada, the Department of Laboratory Medicine, Medicine and Neurology, and Center for Neurogenetics and Neurotherapeutics, University of Washington Medical Center, Seattle, Washington 98195-7110, and the ^¶Buck Institute for Age Research, Novato, California 94945

Spinocerebellar ataxia type 7 is a progressive neurodegenerative disorder caused by a CAG DNA triplet repeat expansion leading to an expanded polyglutamine tract in the ataxin-7 protein. Ataxin-7 appears to be a transcription factor and a component of the STAGA transcription coactivator complex. Here, using live cell imaging and inverted fluorescence recovery after photobleaching, we demonstrate that ataxin-7 has the ability to export from the nucleus via the CRM-1/exportin pathway and that ataxin-7 contains a classic leucine-type nuclear export signal (NES). We have precisely defined the location of this NES in ataxin-7 and found it to be fully conserved in all vertebrate species. Polyglutamine expansion was seen to reduce the nuclear export rate of mutant ataxin-7 relative to wild-type ataxin-7. Subtle point mutation of the NES in polyglutamine expanded ataxin-7 increased toxicity in primary cerebellar neurons in a polyglutamine length-dependent manner in the context of full-length ataxin-7. Our results add ataxin-7 to a growing list of polyglutamine disease proteins that are capable of nuclear shuttling, and we define an activity of ataxin-7 in the STAGA complex of trafficking between the nucleus and cytoplasm.

Received for publication, June 21, 2005 , and in revised form, October 25, 2005.

^* This work was supported by Operating Grant MOP 36518 and a New Scientist Award from the Genetics Institute of the Canadian Institutes of Health Research (to R. T.) and by National Institutes of Health Grants EY14061 (to A. R. L.) and NS40251A (to L. M. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Muscular Dystrophy Association and the Hereditary Disease Foundation.

² A Paul Beeson Physician Faculty Scholar with funding support from the American Federation for Aging Research.

³ To whom correspondence should be addressed. Tel.: 905-525-9140; Fax: 905-522-9033; E-mail: truantr{at}mcmaster.ca.

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