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J. Biol. Chem., Vol. 282, Issue 41, 30150-30160, October 12, 2007

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Proteolytic Cleavage of Ataxin-7 by Caspase-7 Modulates Cellular Toxicity and Transcriptional Dysregulation^*

Jessica E. Young, Launce Gouw, Stephanie Propp, Bryce L. Sopher^¶, Jillian Taylor^||, Amy Lin, Evan Hermel^**, Anna Logvinova, Sylvia F. Chen, Shiming Chen, Dale E. Bredesen, Ray Truant^||, Louis J. Ptacek¹, Albert R. La Spada^¶2, and Lisa M. Ellerby³

From the Buck Institute for Age Research, Novato, California, 94945, Department of Neurology, Howard Hughes Medical Institute, University of California, San Francisco, California 94143, ^¶Departments of Laboratory Medicine, Medicine (Medical Genetics), and Neurology (Neurogenetics), University of Washington Medical Center, Seattle, Washington 98195, ^||McMaster University, Department of Biochemistry and Biomedical Sciences, Hamilton, Ontario L8N 3Z5, Canada, ^**Touro University College of Osteopathic Medicine, Vallejo, California 94592, and Department of Ophthalmology and Visual Sciences, Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

Spinocerebellar ataxia type 7 (SCA7) is a polyglutamine (polyQ) disorder characterized by specific degeneration of cerebellar, brainstem, and retinal neurons. Although they share little sequence homology, proteins implicated in polyQ disorders have common properties beyond their characteristic polyQ tract. These include the production of proteolytic fragments, nuclear accumulation, and processing by caspases. Here we report that ataxin-7 is cleaved by caspase-7, and we map two putative caspase-7 cleavage sites to Asp residues at positions 266 and 344 of the ataxin-7 protein. Site-directed mutagenesis of these two caspase-7 cleavage sites in the polyQ-expanded form of ataxin-7 produces an ataxin-7 D266N/D344N protein that is resistant to caspase cleavage. Although ataxin-7 displays toxicity, forms nuclear aggregates, and represses transcription in human embryonic kidney 293T cells in a polyQ length-dependent manner, expression of the non-cleavable D266N/D344N form of polyQ-expanded ataxin-7 attenuated cell death, aggregate formation, and transcriptional interference. Expression of the caspase-7 truncation product of ataxin-7-69Q or -92Q, which removes the putative nuclear export signal and nuclear localization signals of ataxin-7, showed increased cellular toxicity. We also detected N-terminal polyQ-expanded ataxin-7 cleavage products in SCA7 transgenic mice similar in size to those generated by caspase-7 cleavage. In a SCA7 transgenic mouse model, recruitment of caspase-7 into the nucleus by polyQ-expanded ataxin-7 correlated with its activation. Our results, thus, suggest that proteolytic processing of ataxin-7 by caspase-7 may contribute to SCA7 disease pathogenesis.

Received for publication, June 27, 2007

^* This work is supported by National Institutes of Health Grants NS40251A (to L. M. E.) and EY14061 (to A. R. L.) and Operating Grant MOP 36518 and a New Scientist Award from the Canadian Institutes of Health Research (to R. T.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ An Investigator of the Howard Hughes Medical Institute.

² A Paul Beeson Physician Faculty Scholar recipient from the American Federation of Aging Research.

³ To whom the correspondence should be addressed: The Buck Institute for Age Research, 8001 Redwood Blvd, Novato, CA 94945. Tel.: 415-209-2088; Fax: 415-209-2230; E-mail: lellerby{at}buckinstitute.org.

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