Huntington's Disease (HD) is dominantly inherited neurodegenerative disorder manifested by psychiatric, cognitive and motor symptoms typically starting in mid life and progressing toward death. HD is caused by an expansion of a polyglutamine tract in tile huntingtin protein. The number of diseases caused by polyglutamine expansions continues to, grow and a common mechanism could underlie these disorders. One hypothesis suggests that acting within the nucleus, polyglutamine expansion results in aberrant interactions with nuclear proteins, thereby leading to transcriptional dysregulation. Gene expression arrays on DNA microchips have showed that the scope of transcriptional changes in transgenic HD mice involves different groups of genes, including neurotransmitter receptors. Interestingly, when the known regulatory sequences of these genes were examined it became apparent that they contained binding sites for transcription factor Spl, suggesting that huntingtin may interfere with Spl-mediated transcription. Our preliminary data demonstrate that both normal and mutant huntingtin interact with Spl, whereas only mutant huntingtin significantly inhibits Splmediated transcription of dopamine receptors. In addition, we showed that Spl and its coactivators play a critical role in huntingtin-induced neuronal toxicity. In this work we propose to use our model to accomplish the following Specific Aims: 1) Characterize the specific components of transcriptional machinery required by normal or mutant huntingtin to regulate Spl-mediated expression of dopamine receptors in HD. 2) Examine activity and expression levels of Spl and related factors in transgenic and human HI) brain 3) Determine whether interference by drugs such as mithramycin and HDAC inhibitors with ,Spl-mediated gene transcription may protect against mutant huntingtin. Completion of these aims should reveal new insights into general mechanisms of neurodegeneration and lead to the identification of potential molecular targets for new HI) therapies.

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