Journal article
Hsp27 overexpression in the R6/2 mouse model of Huntington's disease: chronic neurodegeneration does not induce Hsp27 activation
Human molecular genetics, v 16(9), pp 1078-1090
01 May 2007
PMID: 17360721
Featured in Collection : UN Sustainable Development Goals @ Drexel
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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Details
- Title
- Hsp27 overexpression in the R6/2 mouse model of Huntington's disease: chronic neurodegeneration does not induce Hsp27 activation
- Creators
- Alexandra Zourlidou - King's College LondonTali Gidalevitz - Northwestern UniversityMark Kristiansen - MRC Prion UnitChristian Landles - King's College LondonBen Woodman - King's College LondonDominic J. Wells - Charing Cross HospitalDavid S. Latchman - Birkbeck, University of LondonJackie de Belleroche - Charing Cross HospitalSarah J. Tabrizi - MRC Prion UnitRichard I. Morimoto - Northwestern UniversityGillian P. Bates - King's College London
- Publication Details
- Human molecular genetics, v 16(9), pp 1078-1090
- Publisher
- Oxford University Press
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Web of Science ID
- WOS:000247475400008
- Scopus ID
- 2-s2.0-34447331291
- Other Identifier
- 991020099436704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Genetics & Heredity