Huntington's Disease (HD) is an autosomal dominant disorder resulting from selective loss of neurons in the striatum and cerebral cortex. Loss of neurons in HD results from pathological expansion of CAG repeats encoding glutamine. Though the precise mechanisms by which glutamine repeats lead to neuronal loss in HD are unclear, oxidative stress, apoptosis, and transcriptional dysregulation have all been implicated in disease pathogenesis. To understand better oxidative and transcriptional mechanisms that may lead to neuronal loss in HD, we have utilized an in vitro model of oxidative stress in primary cortical neurons. In preliminary studies we have shown that oxidative cell death can be fully abrogated by sequence-selective DNA binding drugs, including mithramycin A (MMA) and chromomcyin A3. These agents are members of the aureolic acid antitumor antibiotics that share a common chromophore, aglycon ring, but differ in the nature of the sugar moieties connected to either side of the aglycone ring. Both antibiotics inhibit transcription during macromoleclar biosynthesis by binding to the """"""""GC"""""""" rich transcriptional response elements. To test whether aureolic antibiotics can protect neurons in an in vivo model ofneurodegeneration that may inolve oxidative stress, we examined the effect of MMA in the R6/2 transgenic model of HD. We found that MMA prolongs survival in these mice by nearly 30%, a magnitude superior to any other single neuroprotective agent. These preliminary data are consistent with the overall hypothesis to be tested in this proposal: MMA inhibits neuronal death due to oxidative stress and/or mutant Huntington protein in vitro and in vivo by inhibiting the binding of pro-apoptotic zinc finger transcription factors such as TIEG, and enhancing the DNA binding of pro-survival transcription factors such as CREB. We will examine this hypothesis by determining whether protective concentrations of MMA inhibit TIEG binding to its GC rich DNA binding sites and whether TIEG is critical for oxidative death in cortical neurons. In the second aim, we will determine how MMA affects CREB DNA binding and whether increases in CREB DNA binding contribute to MMA's salutary effects. In the last specific aim, we will compare the mechanism of neuroprotection of MMA to those ofhistone deacetylase inhibitors, another class of transcriptional regulators. These studies will provide critical, mechanistic data on neuroprotective modulators of transcription.

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Tourette, Cendrine; Farina, Francesca; Vazquez-Manrique, Rafael P et al. (2014) The Wnt receptor Ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity. PLoS Biol 12:e1001895
McFarland, Karen N; Das, Sudeshna; Sun, Ting Ting et al. (2013) Genome-wide increase in histone H2A ubiquitylation in a mouse model of Huntington's disease. J Huntingtons Dis 2:263-77
Taylor, David M; Moser, Roger; Regulier, Etienne et al. (2013) MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition. J Neurosci 33:2313-25
McFarland, Karen N; Das, Sudeshna; Sun, Ting Ting et al. (2012) Genome-wide histone acetylation is altered in a transgenic mouse model of Huntington's disease. PLoS One 7:e41423
Sleiman, Sama F; Langley, Brett C; Basso, Manuela et al. (2011) Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration. J Neurosci 31:6858-70
Hu, Yi; Chopra, Vanita; Chopra, Raman et al. (2011) Transcriptional modulator H2A histone family, member Y (H2AFY) marks Huntington disease activity in man and mouse. Proc Natl Acad Sci U S A 108:17141-6
Ebbel, Erika N; Leymarie, Nancy; Schiavo, Susan et al. (2010) Identification of phenylbutyrate-generated metabolites in Huntington disease patients using parallel liquid chromatography/electrochemical array/mass spectrometry and off-line tandem mass spectrometry. Anal Biochem 399:152-61
Zucker, Birgit; Kama, Jibrin A; Kuhn, Alexandre et al. (2010) Decreased Lin7b expression in layer 5 pyramidal neurons may contribute to impaired corticostriatal connectivity in huntington disease. J Neuropathol Exp Neurol 69:880-95
Benn, Caroline L; Luthi-Carter, Ruth; Kuhn, Alexandre et al. (2010) Environmental enrichment reduces neuronal intranuclear inclusion load but has no effect on messenger RNA expression in a mouse model of Huntington disease. J Neuropathol Exp Neurol 69:817-27
Kim, Jinho; Amante, Daniel J; Moody, Jennifer P et al. (2010) Reduced creatine kinase as a central and peripheral biomarker in Huntington's disease. Biochim Biophys Acta 1802:673-81

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