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J. Biol. Chem., Vol. 283, Issue 12, 7390-7400, March 21, 2008

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Histone Deacetylase Inhibition Modulates Kynurenine Pathway Activation in Yeast, Microglia, and Mice Expressing a Mutant Huntingtin Fragment^*

Flaviano Giorgini¹, Thomas Möller, Wanda Kwan^¶, Daniel Zwilling^¶, Jennifer L. Wacker, Soyon Hong, Li-Chun L. Tsai, Christine S. Cheah, Robert Schwarcz^||, Paolo Guidetti^||, and Paul J. Muchowski^¶**2

From the Departments of Pharmacology and Neurology, University of Washington, Seattle, Washington 98195, ^¶Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, ^||Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21228, and the ^**Departments of Biochemistry and Biophysics and of Neurology, University of California, San Francisco, California 94158

The kynurenine pathway of tryptophan degradation is hypothesized to play an important role in Huntington disease, a neurodegenerative disorder caused by a polyglutamine expansion in the protein huntingtin. Neurotoxic metabolites of the kynurenine pathway, generated in microglia and macrophages, are present at increased levels in the brains of patients and mouse models during early stages of disease, but the mechanism by which kynurenine pathway up-regulation occurs in Huntington disease is unknown. Here we report that expression of a mutant huntingtin fragment was sufficient to induce transcription of the kynurenine pathway in yeast and that this induction was abrogated by impairing the activity of the histone deacetylase Rpd3. Moreover, numerous genetic suppressors of mutant huntingtin toxicity that are functionally unrelated converged unexpectedly on the kynurenine pathway, supporting a critical role for the kynurenine pathway in mediating mutant huntingtin toxicity in yeast. Histone deacetylase-dependent regulation of the kynurenine pathway was also observed in a mouse model of Huntington disease, in which treatment with a neuroprotective histone deacetylase inhibitor blocked activation of the kynurenine pathway in microglia expressing a mutant huntingtin fragment in vitro and in vivo. These findings suggest that a mutant huntingtin fragment can perturb transcriptional programs in microglia, and thus implicate these cells as potential modulators of neurodegeneration in Huntington disease that are worthy of further investigation.

Received for publication, October 2, 2007 , and in revised form, November 30, 2007.

^* 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 HighQ Foundation, Medical Research Council, and the Royal Society. Present address: Dept. of Genetics, University of Leicester, Leicester LE1 7RH, UK.

² Supported by NINDS, National Institutes of Health and the HighQ Foundation. To whom correspondence should be addressed: Gladstone Institute of Neurological Disease, Depts. of Biochemistry and Biophysics and of Neurology, University of California, San Francisco, 1650 Owens St., San Francisco, CA 94158. Tel.: 415-734-2515; Fax: 415-355-0824; E-mail: pmuchowski{at}gladstone.ucsf.edu.

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