Abstract |
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.
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Authors | Alexandra Zourlidou, Tali Gidalevitz, Mark Kristiansen, Christian Landles, Ben Woodman, Dominic J Wells, David S Latchman, Jackie de Belleroche, Sarah J Tabrizi, Richard I Morimoto, Gillian P Bates |
Journal | Human molecular genetics
(Hum Mol Genet)
Vol. 16
Issue 9
Pg. 1078-90
(May 01 2007)
ISSN: 0964-6906 [Print] England |
PMID | 17360721
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Heat-Shock Proteins
- Transglutaminases
- Aconitate Hydratase
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Topics |
- Aconitate Hydratase
(metabolism)
- Animals
- Behavior, Animal
- Blotting, Western
- Brain
(metabolism, pathology)
- Disease Models, Animal
- Female
- Gene Expression
- Genotype
- Heat-Shock Proteins
(genetics, metabolism)
- Heat-Shock Response
(genetics, physiology)
- Huntington Disease
(genetics, metabolism, physiopathology)
- Immunohistochemistry
- Immunoprecipitation
- Inclusion Bodies
(metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred CBA
- Mice, Knockout
- Mice, Transgenic
- Nerve Degeneration
(genetics, metabolism, physiopathology)
- Oxidative Stress
- Phenotype
- Transglutaminases
(genetics, metabolism)
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