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

Bett, J. S., Benn, C. L., Ryu, K.-Y., Kopito, R. R. and Bates, G. P. (2009) The polyubiquitinUbcgene modulates histone H2A monoubiquitylation in the R6/2 mouse model of Huntington's disease. Journal of Cellular and Molecular Medicine, 13(8b), pp. 2645-2657. (doi:10.1111/j.1582-4934.2008.00543.x)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bett, Dr John
Authors: Bett, J. S., Benn, C. L., Ryu, K.-Y., Kopito, R. R., and Bates, G. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Journal of Cellular and Molecular Medicine
Publisher:John Wiley & Sons Ltd
ISSN:1582-1838
ISSN (Online):1582-4934
Copyright Holders:Copyright © 2008 The Authors
First Published:First published in Journal of Cellular and Molecular Medicine 13(8b):2645-2657
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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