Accumulation of pathogenic proteins and peptides with expanded polyglutamine repeats is characteristic of Huntington's disease (HD) and related neurodegenerative diseases. Other than the fact that a polyQ expansion within the disease protein causes disease, the major cellular mechanisms of pathogenesis are not clear. Multiple cellular processes have been implicated, but proximal causative events have proven difficult to distinguish from distal correlative events. As polyQ disease proteins can be modified in ways that change their cellular function or fate, it is likely that Htt protein modifications contribute to pathology. We find that Htt can be SUMO modified and that this modification can affect its biochemical properties and pathogenic potential in a Drosophila model. These observations form the rationale for this proposal. I propose to investigate, in depth, the role of SUMOylation in HD pathogenesis and to investigate the biochemical mechanisms involved in the SUMO-1 modification and de-SUMOylation of mutant Htt using a multidisciplinary approach. Implicit in this research will be an effort to identify potential therapeutic targets and develop strategies for interventions that disrupt or prevent pathology in the biochemical pathways responsible for alteration of mutant Htt. Hypothesis 1: SUMO modification of Htt is involved in HD phenotypes Mutant Htt accumulates in the nuclei of neurons and induces the dysregulation of key cellular processes including transcription. The impact of SUMOylation of mutant Htt upon cellular functions will be tested using in vitro and in vivo systems. Hypothesis 2: Specific E3-SUMO ligases are responsible for SUMO modification of Htt. An overall reduction of SUMOylation suppresses pathogenesis in vivo, therefore the identification of the specific enzymes involved in the attachment of SUMO groups to the Htt protein or in the removal of SUMO from the Htt protein may provide novel therapeutic targets for treatment of HD. Hypothesis 3: SUMO modification of Htt is critical to disease pathogenesis in vivo. Here we will test the physiologic relevance of SUMO modification pathways in Drosophila.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052789-05
Application #
7849779
Study Section
Special Emphasis Panel (ZRG1-NDBG-E (08))
Program Officer
Sutherland, Margaret L
Project Start
2006-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$329,842
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Ochaba, Joseph; Monteys, Alex Mas; O'Rourke, Jacqueline G et al. (2016) PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington's Disease-Associated Phenotypes In Vivo. Neuron 90:507-20
Lee, John H; Tecedor, Luis; Chen, Yong Hong et al. (2015) Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes. Neuron 85:303-15
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
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
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
Sontag, Emily M; Joachimiak, Lukasz A; Tan, Zhiqun et al. (2013) Exogenous delivery of chaperonin subunit fragment ApiCCT1 modulates mutant Huntingtin cellular phenotypes. Proc Natl Acad Sci U S A 110:3077-82
Sontag, Emily Mitchell; Lotz, Gregor P; Yang, Guocheng et al. (2012) Detection of Mutant Huntingtin Aggregation Conformers and Modulation of SDS-Soluble Fibrillar Oligomers by Small Molecules. J Huntingtons Dis 1:127-140
Bodai, Laszlo; Pallos, Judit; Thompson, Leslie Michels et al. (2012) Pcaf modulates polyglutamine pathology in a Drosophila model of Huntington's disease. Neurodegener Dis 9:104-6
Sontag, Emily Mitchell; Lotz, Gregor P; Agrawal, Namita et al. (2012) Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington's disease models. J Neurosci 32:11109-19
Jia, Haiqun; Kast, Ryan J; Steffan, Joan S et al. (2012) Selective histone deacetylase (HDAC) inhibition imparts beneficial effects in Huntington's disease mice: implications for the ubiquitin-proteasomal and autophagy systems. Hum Mol Genet 21:5280-93

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