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J. Biol. Chem., Vol. 281, Issue 24, 16672-16680, June 16, 2006

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Sp1 Is Up-regulated in Cellular and Transgenic Models of Huntington Disease, and Its Reduction Is Neuroprotective^*

Zhihua Qiu, Fran Norflus, Bhupinder Singh, Mary K. Swindell, Rodica Buzescu, Michelle Bejarano, Raman Chopra, Birgit Zucker, Caroline L. Benn, Derek P. DiRocco, Jang-Ho J. Cha, Robert J. Ferrante^¶, and Steven M. Hersch¹

From the Massachusetts General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, the Geriatric Research Education and Clinical Center, Bedford Veterans Affairs Medical Center, Bedford, Massachusetts 01730, and the ^¶Neurology, Anatomy and Neurobiology, Pathology, and Psychiatry Departments, Boston University School of Medicine, Boston, Massachusetts 02118

Interactions between mutant huntingtin (Htt) and a variety of transcription factors including specificity proteins (Sp) have been suggested as a central mechanism in Huntington disease (HD). However, the transcriptional activity induced by Htt in neurons that triggers neuronal death has yet to be fully elucidated. In the current study, we characterized the relationship of Sp1 to Htt protein aggregation and neuronal cell death. We found increased levels of Sp1 in neuronal-like PC12 cells expressing mutant Htt, primary striatal neurons, and brain tissue of HD transgenic mice. Sp1 levels were also elevated when 3-nitropropionate (3-NP) was used to induce cell death in PC12 cells. To assess the effects of knocking down Sp1 in HD pathology, we used Sp1 siRNA, a heterozygous Sp1 knock-out mouse, and mithramycin A, a DNA-intercalating agent that inhibits Sp1 function. The three approaches consistently yielded reduced levels of Sp1 which ameliorated toxicity caused by either mutant Htt or 3-NP. In addition, when HD mice were crossed with Sp1 heterozygous knock-out mice, the resulting offspring did not experience the loss of dopamine D2 receptor mRNA characteristic of HD mice, and survived longer than their HD counterparts. Our data suggest that enhancement of transcription factor Sp1 contributes to the pathology of HD and demonstrates that its suppression is beneficial.

Received for publication, October 27, 2005 , and in revised form, March 8, 2006.

^* This work was supported by National Institutes of Health Grants NS35255 (to S. M. H.), AT00613 and NS045242 (to S. M. H., D. K., J.-H. J. C., and R. J. F.), NS045806 (to R. J. F.); NINDS, National Institutes of Health Grant NS038106 (to J.-H. J. C.); the Huntington's Disease Society of America (to S. M. H., J.-H. J. C., and R. J. F.), Glendorn Foundation (to J.-H. J. C.), Hereditary Disease Foundation, the Jerry McDonald Research Fund in Huntington's Disease, and the Veterans Administration (to R. J. F.). 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 data.

¹ To whom correspondence should be addressed: Mass General Institute for Neurodegenerative Disease MGH E., Bldg. 114, Suite 2001, 114 16th St., Charlestown, MA 02129. Tel.: 617-726-1254; Fax: 617-724-1480; E-mail: hersch{at}helix.mgh.harvard.edu.

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