• Open Access

The polyubiquitin Ubc gene modulates histone H2A monoubiquitylation in the R6/2 mouse model of Huntington's disease

Authors

  • John S. Bett,

    1. King's College London School of Medicine, Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
    Search for more papers by this author
  • Caroline L. Benn,

    1. King's College London School of Medicine, Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
    Search for more papers by this author
  • Kwon-Yul Ryu,

    1. Department of Biological Sciences, Stanford University, Stanford, CA, USA
    Search for more papers by this author
    • Present address: Department of Life Science, University of Seoul, 130–743, Korea.

  • Ron R. Kopito,

    1. Department of Biological Sciences, Stanford University, Stanford, CA, USA
    Search for more papers by this author
  • Gillian P. Bates

    Corresponding author
    1. King's College London School of Medicine, Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
      Correspondence to: Gillian P. BATES,
      Medical and Molecular Genetics,
      King's College London School of Medicine,
      8th Floor Tower Wing, Guy's Hospital,
      London SE1 9RT, UK.
      Tel.: +44 2071883722
      Fax: +44 2071882585
      E-mail: gillian.bates@genetics.kcl.ac.uk
    Search for more papers by this author

Correspondence to: Gillian P. BATES,
Medical and Molecular Genetics,
King's College London School of Medicine,
8th Floor Tower Wing, Guy's Hospital,
London SE1 9RT, UK.
Tel.: +44 2071883722
Fax: +44 2071882585
E-mail: gillian.bates@genetics.kcl.ac.uk

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disease caused by the expansion of a polyglutamine tract in the protein huntingtin (htt). HD brains are characterized by the presence of ubiquitin-positive neuronal inclusion bodies, suggesting that disturbances in the distribution of cellular ubiquitin may contribute to disease pathology. The fact that several neurodegenerative diseases are caused by mutations in ubiquitin-processing enzymes and that the polyubiquitin genes are required for resistance to cellular stress led us to investigate the effect of perturbing the ubiquitin system in HD. We crossed R6/2 transgenic HD mice with heterozygous polyubiquitin Ubc knockout mice (Ubc+/−) and assessed the effect on the R6/2 neurological phenotype. Although the R6/2 phenotype was largely unaffected, surprisingly we observed some subtle improvements in various behavioural activities correlating with heterozygous Ubc knockout. Interestingly, immunoblot analysis revealed that the levels of monoubiquitylated histone H2A (uH2A), a modification associated with gene repression, were significantly increased in the brains of R6/2 mice. Furthermore, the reduction of Ubc expression in R6/2; Ubc+/− mice largely prevented this increase in uH2A levels. However, we were not able to show by the use of a limited number of quantitative RT-PCR assays that changes in the amount of uH2A in the R6/2-Ubc mice had an effect on disease-associated transcriptional abnormalities. These results suggest that the expression of aggregation-prone mutant htt causes disturbances to the ubiquitin system, which may contribute to disease due to the diverse and important roles of ubiquitin.

Ancillary