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. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. doi 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
  7. 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
  8. 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
  9. 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
  10. 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

Scientific Experts

  • J Marsh
  • Leslie Michels Thompson
  • Joan S Steffan
  • Judit Pallos
  • Barbara L Apostol
  • Charity T Aiken
  • Tamas Lukacsovich
  • Katalin Illes
  • Natalia Slepko
  • Ya Zhen Zhu
  • Xiaofeng Gu
  • Steven Finkbeiner
  • Hasan Khashwji
  • Lan Huang
  • Ronald Wetzel
  • Erica Rockabrand
  • Laszlo Bodai
  • Aleksey Kazantsev
  • Urvee A Desai
  • Frank LaFerla
  • Kim N Green
  • Judy M Purcell
  • Erin R Greiner
  • Scott O Zeitlin
  • Donald C Lo
  • Michael R Hayden
  • Jacqueline Gire O'Rourke
  • Namita Agrawal
  • Cortnie M Guerrero
  • Gillian Bates
  • Ravindra Kodali
  • Alice L Lau
  • Ali Khoshnan
  • Danielle Simmons
  • Alex Osmand
  • X William Yang
  • Frank M LaFerla
  • Ashish Massey
  • Paul H Patterson
  • Rakesh Mishra
  • Montserrat Arrasate
  • Kim Green
  • Linda S Kaltenbach
  • Ana Maria Cuervo
  • Marta Martinez-Vincente
  • Kimia Menhaji
  • Margaret Roarke
  • Catarina Ramos
  • Paola Conforti
  • Judith M Purcell
  • Danielle A Simmons
  • Elena Cattaneo
  • Chiara Zuccato
  • Malcolm Casale
  • Satish Kathuria
  • Antonello Pantalone
  • Stefano L Sensi
  • Patrick G Sullivan
  • Vidya N Nukala
  • Anusri M Bhattacharyya
  • Aye Aye K Ma
  • Brent R Stockwell
  • James M Olson
  • Erik S Schweitzer
  • Marc I Diamond
  • Andrew Strand
  • Jun Wu
  • George R Jackson

Detail Information

Publications11

  1. 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...
  2. 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...
  3. 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...
  4. 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...
  5. 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...
  6. doi 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...
  7. 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...
  8. 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...
  9. 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...
  10. 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...
  11. 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...