Protein acetylation in Huntington's disease

Summary

Principal Investigator: J Marsh
Affiliation: University of California
Country: USA
Abstract: 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 Huntington's disease 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 Huntington's disease 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 (approximately 11 HATs and approximately 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.
Funding Period: 2002-12-01 - 2007-11-30
more information: NIH RePORT

Top Publications

  1. pmc A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease
    Marianne R Smith
    Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA
    Hum Mol Genet 23:2995-3007. 2014
  2. pmc Targeting H3K4 trimethylation in Huntington disease
    Malini Vashishtha
    Department of Psychiatry and Human Behavior and UCI Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA
    Proc Natl Acad Sci U S A 110:E3027-36. 2013
  3. pmc SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation
    Jacqueline Gire O'Rourke
    Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA
    Cell Rep 4:362-75. 2013
  4. pmc Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's disease
    Haiqun Jia
    Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Neurobiol Dis 46:351-61. 2012
  5. pmc Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration
    Sama F Sleiman
    Burke Medical Research Institute, White Plains, New York 10605, USA
    J Neurosci 31:6858-70. 2011
  6. pmc Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Aβ oligomers
    Rakez Kayed
    Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697 3900, USA
    Mol Neurodegener 5:57. 2010
  7. pmc Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease
    Stephen J McConoughey
    Burke Medical Research Institute, White Plains, NY, USA
    EMBO Mol Med 2:349-70. 2010
  8. pmc ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease
    Pamela Maher
    Department of Cellular Neurobiology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
    Hum Mol Genet 20:261-70. 2011
  9. pmc Pcaf modulates polyglutamine pathology in a Drosophila model of Huntington's disease
    Laszlo Bodai
    Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA
    Neurodegener Dis 9:104-6. 2012
  10. pmc A novel target for Huntington's disease: ERK at the crossroads of signaling. The ERK signaling pathway is implicated in Huntington's disease and its upregulation ameliorates pathology
    Laszlo Bodai
    Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary
    Bioessays 34:142-8. 2012

Scientific Experts

  • Laszlo Bodai
  • Pamela A Maher
  • J Marsh
  • Ruth Luthi-Carter
  • Leslie Michels Thompson
  • Judit Pallos
  • Joan S Steffan
  • Tamas Lukacsovich
  • Barbara L Apostol
  • Leslie M Thompson
  • Katalin Illes
  • Malini Vashishtha
  • Jacqueline Gire O'Rourke
  • Sama F Sleiman
  • Ya Zhen Zhu
  • Steven Finkbeiner
  • Charity T Aiken
  • Natalia Slepko
  • Marianne R Smith
  • Adeela Syed
  • Gillian P Bates
  • Wan Song
  • Ghazaleh Sadri-Vakili
  • Alice Lau
  • Haiqun Jia
  • Lata Mahishi
  • Manuela Basso
  • Li Xia
  • Brett C Langley
  • Giovanni Coppola
  • Rajiv R Ratan
  • Daniel H Geschwind
  • Stephen J McConoughey
  • Rakez Kayed
  • Giulia Ossato
  • Xiaofeng Gu
  • Hasan Khashwji
  • Lan Huang
  • Ronald Wetzel
  • Erica Rockabrand
  • Aleksey Kazantsev
  • Urvee A Desai
  • Shane A Worthge
  • Sylvie Ramboz
  • Enrica Diodato
  • S J Tabrizi
  • Stephen R Wei
  • Carol Murphy
  • Giuseppe Pollio
  • Liliana Menalled
  • Letizia Magnoni
  • Davide Franceschini
  • Goran Westerberg
  • Ozgun Gokce
  • Bernard Landwehrmeyer
  • Judy Purcell
  • Marco Gianfriddo
  • Russell Thomas
  • Brett A Barbaro
  • Luisa Massai
  • Michela Camarri
  • Andrea Caricasole
  • Carla Scali
  • Tamas Rasko
  • Christopher D Lima
  • Thomas Peter Nicholson
  • Theresa A Gipson
  • Ferah Yildirim
  • Juan Troncosco
  • Jaclyn R Gareau
  • Dimitri Krainc
  • Annie Vogel-Ciernia
  • Christopher W Ng
  • Ian H Kratter
  • David Reverter
  • David E Housman
  • John Lee
  • Joseph Ochaba
  • Erich E Wanker
  • Ernest Fraenkel
  • Lisa Mee
  • Adam Labadorf
  • Christopher A Ross
  • Beverly Davidson
  • Marian DiFiglia
  • Alex Mas Monteys
  • Mary Dasso
  • James R Rusche
  • Shayna B Darnell
  • Judith Purcell

Detail Information

Publications23

  1. pmc A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease
    Marianne R Smith
    Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA
    Hum Mol Genet 23:2995-3007. 2014
    ....
  2. pmc Targeting H3K4 trimethylation in Huntington disease
    Malini Vashishtha
    Department of Psychiatry and Human Behavior and UCI Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA
    Proc Natl Acad Sci U S A 110:E3027-36. 2013
    ..Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD. ..
  3. pmc SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation
    Jacqueline Gire O'Rourke
    Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA
    Cell Rep 4:362-75. 2013
    ....
  4. pmc Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's disease
    Haiqun Jia
    Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Neurobiol Dis 46:351-61. 2012
    ..These results suggest that inhibition of HDACs 1 and 3 can relieve HD-like phenotypes in model systems and that HDAC inhibitors targeting these isotypes might show therapeutic benefit in human HD...
  5. pmc Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration
    Sama F Sleiman
    Burke Medical Research Institute, White Plains, New York 10605, USA
    J Neurosci 31:6858-70. 2011
    ..These results support a model in which cancer cell transformation shares key genetic components with neurodegeneration...
  6. pmc Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Aβ oligomers
    Rakez Kayed
    Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697 3900, USA
    Mol Neurodegener 5:57. 2010
    ..Recent evidence suggests that soluble amyloid oligomers and not the insoluble amyloid fibrils may represent the primary pathological species of protein aggregates...
  7. pmc Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease
    Stephen J McConoughey
    Burke Medical Research Institute, White Plains, NY, USA
    EMBO Mol Med 2:349-70. 2010
    ..Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC-independent epigenetic strategy for treating neurodegeneration...
  8. pmc ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease
    Pamela Maher
    Department of Cellular Neurobiology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
    Hum Mol Genet 20:261-70. 2011
    ..Thus, fisetin, resveratrol and related compounds might be useful for the treatment of HD by virtue of their unique ability to activate ERK...
  9. pmc Pcaf modulates polyglutamine pathology in a Drosophila model of Huntington's disease
    Laszlo Bodai
    Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA
    Neurodegener Dis 9:104-6. 2012
    ....
  10. pmc A novel target for Huntington's disease: ERK at the crossroads of signaling. The ERK signaling pathway is implicated in Huntington's disease and its upregulation ameliorates pathology
    Laszlo Bodai
    Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary
    Bioessays 34:142-8. 2012
    ..Some of this cellular complexity can be capitalized on to achieve selective activation of ERK, which can be protective...
  11. pmc A two-step path to inclusion formation of huntingtin peptides revealed by number and brightness analysis
    Giulia Ossato
    Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California, Irvine, California, USA
    Biophys J 98:3078-85. 2010
    ..The behavior of Httex1p in COS-7 and ST14A cells is compared...
  12. pmc SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis
    Ruth Luthi-Carter
    Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, 1015 Lausanne, Switzerland
    Proc Natl Acad Sci U S A 107:7927-32. 2010
    ..Furthermore, the ascertainment of SIRT2's role in regulating cellular metabolism demonstrates a central function shared with other sirtuin proteins...
  13. pmc Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice
    Xiaofeng Gu
    Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA
    Neuron 64:828-40. 2009
    ..Together, our findings demonstrate that serines 13 and 16 are critical determinants of fl-mhtt-induced disease pathogenesis in vivo, supporting the targeting of huntingtin NT17 domain and its modifications in HD therapy...
  14. ncbi Biologically active molecules that reduce polyglutamine aggregation and toxicity
    Urvee A Desai
    Department of Neurology and Cellular and Molecular Pharmacology, San Francisco, CA 94143 2280, USA
    Hum Mol Genet 15:2114-24. 2006
    ..The high predictive value of the primary screen suggests that the FRET-based screening assay may be useful for further primary and secondary screens for genes or small molecules that inhibit polyglutamine protein aggregation...
  15. pmc Normal-repeat-length polyglutamine peptides accelerate aggregation nucleation and cytotoxicity of expanded polyglutamine proteins
    Natalia Slepko
    Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697 4260, USA
    Proc Natl Acad Sci U S A 103:14367-72. 2006
    ..The results suggest that the overall state of the polyGln protein network in a cellular environment may have a profound effect on the toxic consequences of polyGln expansion and thus may serve as a genetic modifier of age of onset in HD...
  16. ncbi Drosophila in the study of neurodegenerative disease
    J Lawrence Marsh
    Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California 92697 2300, USA
    Neuron 52:169-78. 2006
    ..This review highlights selected recent applications to illustrate the use of Drosophila in studying neurodegenerative diseases...
  17. ncbi The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis
    Erica Rockabrand
    Department of Psychiatry and Human Behavior, University of California, Gillespie 2121, Irvine, CA 92697, USA
    Hum Mol Genet 16:61-77. 2007
    ..Interestingly, neither mitochondrial nor ER associations seem to be required to promote long-term [Ca2+]i dyshomeostasis...
  18. ncbi CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice
    Barbara L Apostol
    Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA
    Mol Cell Neurosci 39:8-20. 2008
    ..These studies suggest a novel therapeutic approach for a currently untreatable neurodegenerative disease, HD, via CEP-1347 up-regulation of BDNF...
  19. pmc Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington's disease
    Judit Pallos
    Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA
    Hum Mol Genet 17:3767-75. 2008
    ..These results highlight a novel therapeutic approach for HD in the form of Sir2 inhibition and possible combinatorial inhibition of Sir2 and Rpd3...
  20. pmc Animal models of polyglutamine diseases and therapeutic approaches
    J Lawrence Marsh
    Developmental Biology Center and the Department of Developmental and Cell Biology, University of California, Irvine, California 92697, USA
    J Biol Chem 284:7431-5. 2009
    ..Here, we describe polyglutamine repeat diseases that have been modeled in a variety of organisms, including worms, flies, mice, and non-human primates, and discuss examples of how they have broadened the therapeutic landscape...
  21. pmc Phosphorylation of threonine 3: implications for Huntingtin aggregation and neurotoxicity
    Charity T Aiken
    Department of Developmental and Cell Biology, University of California, Irvine, California 92697, USA
    J Biol Chem 284:29427-36. 2009
    ..Thus, therapeutic strategies that modulate these events could in turn affect Htt pathogenesis...
  22. pmc IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome
    Leslie Michels Thompson
    Department of Psychiatry and Human Behavior, University of California, Irvine, 92697, USA
    J Cell Biol 187:1083-99. 2009
    ..Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species...
  23. ncbi Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity
    Barbara L Apostol
    Department of Psychiatry and Human Behavior, University of California, Irvine, 92697, USA
    Hum Mol Genet 15:273-85. 2006
    ..These studies suggest that pharmacological intervention in MAPK pathways, particularly at the level of ERK activation, may be an appropriate approach to HD therapy...