title: Hsp27 overexpression in the R6/2 mouse model of Huntington's disease: chronic neurodegeneration does not induce Hsp27 activation.
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.
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, School of Medicine, London SE1 9RT, UK.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zourlidou
authors.forename: Tali
authors.initials: T
authors.lastname: Gidalevitz
authors.forename: Mark
authors.initials: M
authors.lastname: Kristiansen
authors.forename: Christian
authors.initials: C
authors.lastname: Landles
authors.forename: Ben
authors.initials: B
authors.lastname: Woodman
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Wells
authors.forename: David S
authors.initials: DS
authors.lastname: Latchman
authors.forename: Jackie
authors.initials: J
authors.lastname: de Belleroche
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D018869:Heat-Shock Response / Q000235:genetics / Q000502:physiology; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D002479:Inclusion Bodies / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018384:Oxidative Stress; D010641:Phenotype; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism
chemical_list: D006360:Heat-Shock Proteins; D011503:Transglutaminases; D000154:Aconitate Hydratase