Huntington's disease (HD) is a progressive and fatal neurological disorder caused by an expanded CAG repeat in the gene coding for a protein of unknown function, huntingtin (HD). There is no known treatment for HD. Although the exact cause of neuronal death in HD remains unknown, there is substantial evidence linking oxidative stress, apoptosis, mitochonddal and energy metabolism dysfunction, and excitotoxicity. These events may be secondary to transcriptional dysregulation caused by direct binding of the mutant HD protein or cleaved products to DNA. Altered protein-protein interactions associated with mutant htt are a consistent finding in HD. Mutant htt recruits other proteins into insoluble aggregates. Mutant HD-induced transcriptional dysregulation may occur early on in the disease process, altering gene expression in those pathogenic mechanisms proposed in HD and causing subsequent neuronal death. We hypothesize that compounds that inhibit or modify transcription factors and also prevent their sequestration may provide novel therapeutic interventions in HD. This hypothesis is based on our novel preliminary data that mithramycin A, an aureolic acid antibiotic that inhibits transcriptional initiation; sodium butyrate, a histone deacetylase inhibitor that modifies transcription by reducing levels of acetylated histones; and cystamine, which blocks huntingtin aggregation, are all effective in significantly extending survival and delaying the neuropathological phenotype in transgeniC HD mice. We will examine the therapeutic effects of mithramycin A and its analogs in HD mouse models, determine optimal intraperitoneal dosing, and complete cross-longitudinal studies on behavioral and neuropathological outcome measures, as pre-clinical trials for human studies. We will compare treatment started both before and after clinical symptoms appear. Secondly, we will characterize the efficacy of histone deacetylase inhibitors and determine whether their administration will improve the clinical and neuropathological phenotype found in transgenic HD mice. Lastly, we propose to identify any cumulative synergies using mithramycin and HDAC inhibitors, while using these compounds in combination with cystamine in targeting eady molecular events in the pathogenesis of HD. Cystamine significantly reduces huntingtin aggregates in HD mice and early treatment may reduce transcription factor sequestration, preventing relocalization of transcription factors, co-activators, and repressor proteins over the temporal sequence of disease in HD mice. This combined multi-pharmaceutical treatment may have a significant neuroprotective effect in HD mice and provide preclinical data for prospective clinical drug-trials in HD patients.
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