EXCEED THE SPACE PROVIDED. Huntington's disease (HD) and other expanded polyglutamine diseases are late- onset neurodegenerative diseases caused by expansion of a glutamine repeat in the mutant protein. Currently, no cure or effective treatment for these agonizing and lethal diseases exists. The pathogenic target of the expanded glutamine repeat is unknown. We find that the polyglutamine domain of Huntingtin (Htt) binds to and inhibits the activity of several acetyltransferases (e.g.CBP, p300, and P/CAF) and reduces the level of acetylated histones in cell culture. We have developed and used two Drosophila models of HD to test the possibility that neuropathology may result from reduced levels of acetylation and transcription. We find that inhibition of the deacetylation process by two independent mechanisms Le. genetically or pharmacologically (HDAC inhibitors) reduces lethality and arrests photoreceptor neuron degeneration. These results strongly implicate the state of acetylation in the pathogenic process. As several HDAC inhibitors, including SAHA, are currently FDA approved for use in other clinical settings or are in Phase I clinical trials, HDAC inhibitors can now be seriously considered as potential therapeutic agents for HD and related diseases. This represents one of the early cases where potentially useful pharmacologic agents have been identified in a Drosophila model of disease. Here we propose to extend these studies using the Drosophila model. In both flies and man there are families of HAT (Histone Acetyl Transferase) and HDAC (Histone DeACetylase) genes (-11 HATs and ~9 HDAC related genes). In this project, we will determine whether all or just some of these genes are relevant to polyglutamine pathogenesis and we will determine whether contributions are additive. These data will improve our understanding of the genetic and molecular basis of pathogenesis, they will identify new targets for therapeutics and they will reveal whether combination therapies targeted at multiple enzymes in the HAT/HDAC cycle might be effective. PERFORMANCSEITE(S)(organizatiocnit,ys, tate) University of California, Irvine, Irvine, CA 92697 KEY PERSONNEL ========================================Section End===========================================
| Song, Wan; Zsindely, Nóra; Faragó, Anikó et al. (2018) Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington's disease. Hum Mol Genet 27:649-666 |
| Chongtham, Anjalika; Barbaro, Brett; Filip, Tomas et al. (2018) Nonmammalian Models of Huntington's Disease. Methods Mol Biol 1780:75-96 |
| Arystarkhova, Elena; Sweadner, Kathleen J (2016) Functional Studies of Na(+),K(+)-ATPase Using Transfected Cell Cultures. Methods Mol Biol 1377:321-32 |
| Sweadner, Kathleen J (2016) Colorimetric Assays of Na,K-ATPase. Methods Mol Biol 1377:89-104 |
| Barbaro, Brett A; Lukacsovich, Tamas; Agrawal, Namita et al. (2015) Comparative study of naturally occurring huntingtin fragments in Drosophila points to exon 1 as the most pathogenic species in Huntington's disease. Hum Mol Genet 24:913-25 |
| Ochaba, Joseph; Lukacsovich, Tamás; Csikos, George et al. (2014) Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc Natl Acad Sci U S A 111:16889-94 |
| Smith, Marianne R; Syed, Adeela; Lukacsovich, Tamas et al. (2014) A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease. Hum Mol Genet 23:2995-3007 |
| Vashishtha, Malini; Ng, Christopher W; Yildirim, Ferah et al. (2013) Targeting H3K4 trimethylation in Huntington disease. Proc Natl Acad Sci U S A 110:E3027-36 |
| Steele, J W; Lachenmayer, M L; Ju, S et al. (2013) Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model. Mol Psychiatry 18:889-97 |
| O'Rourke, Jacqueline Gire; Gareau, Jaclyn R; Ochaba, Joseph et al. (2013) SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep 4:362-75 |
Showing the most recent 10 out of 32 publications
