Hsp27 overexpression in the R6/2 mouse model of Huntington's disease: chronic neurodegeneration does not induce Hsp27 activation

• Published in: Human molecular genetics 2007-05, Vol.16 (9), p.1078-1090
• Main Authors: Zourlidou, Alexandra, Gidalevitz, Tali, Kristiansen, Mark, Landles, Christian, Woodman, Ben, Wells, Dominic J., Latchman, David S., de Belleroche, Jackie, Tabrizi, Sarah J., Morimoto, Richard I., Bates, Gillian P.
• Format: Article
• Language: English
• Subjects: Aconitate Hydratase - metabolism; Animals; Behavior, Animal; Biological and medical sciences; Blotting, Western; Brain - metabolism; Brain - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Heat-Shock Response - genetics; Heat-Shock Response - physiology; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington Disease - physiopathology; Immunohistochemistry; Immunoprecipitation; Inclusion Bodies - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Transgenic; Molecular and cellular biology; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; Nerve Degeneration - physiopathology; Neurology; Oxidative Stress; Phenotype; Transglutaminases - genetics; Transglutaminases - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddm057

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 formation and cell death. To investigate this in vivo, we conducted an extensive phenotypic characterization 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.