Human Molecular Genetics Advance Access published online on March 14, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm057
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Hsp27 overexpression in the R6/2 mouse model of Huntington's Disease: Chronic Neurodegeneration does not Induce Hsp27 Activation
1 King's College London, Department of Medical and Molecular Genetics, School of Medicine, London, SE1 9RT, UK 2 Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, IL 60208, USA 3 Department of Neurodegenerative Disease, MRC Prion Unit, Institute of Neurology, Queen Square, London, WC1N 3BG 4 Division of Neuroscience and Psychological Medicine, Faculty of Medicine, Imperial College London, Charing Cross Hospital, London W6 8RF, UK 5 Birkbeck College, University of London, Malet Street, London, WC1E 7HX, UK
* To whom correspondence should be addressed at: Medical and Molecular Genetics, King's College London School of Medicine, 8th floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK. Tel: +44 2071883722; Fax: +44 2071882585; Email: gillian.bates{at}genetics.kcl.ac.uk
Received November 10, 2006; Revised March 2, 2007; Accepted March 2, 2007
Huntington's disease (HD) is caused by an expanded polyglutamine tract in the huntingtin protein. Mitochondrial dysfunction and free radical damage occur in both R6/2 mice and HD patient brains and might play a role in disease pathogenesis. In cell culture systems, heat shock protein 27 (Hsp27), a small molecular chaperone, suppresses mutant huntingtin-induced reactive oxygen species (ROS) formation and cell death. To investigate this in vivo we conducted an extensive phenotypic characterisation of mice arising from a cross between R6/2 mice and Hsp27 transgenic mice but did not observe an improvement of the R6/2 phenotype. Hsp27 overexpression had no effect in reducing oxidative stress in the R6/2 brain, assessed by measuring striatal aconitase activity and protein carbonylation levels. Native protein gel analysis revealed that transgenic Hsp27 forms active, large oligomeric species in heat shocked brain lysates demonstrating that it is efficiently activated upon stress. In contrast, Hsp27 in double transgenic brains exists predominantly as a low molecular weight, inactive species. This suggests that Hsp27, which is otherwise activatable upon heat shock, remains inactive in the R6/2 model of chronic neurodegeneration. Hsp27 transgenics had been previously shown to be protected from acute stresses such as kainate administration, ischemia/reperfusion heart injury and neonatal nerve injury. Our study is the first to suggest a differential modulation of Hsp27 activation in vivo and, importantly, it illustrates the diverse effect of Hsp27 on acute versus chronic models of disease.
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