title: Cytochrome C and caspase-9 expression in Huntington's disease.
abstract: There is increasing evidence implicating apoptosis-mediated cell death in the pathogenesis of neurodegenerative diseases. One important event in the apoptotic cascade is the release of cytochrome c by mitochondria into the cytoplasm, activating caspase-9, leading to the subsequent activation of downstream executioner caspases. In the present study, we examined the distribution of cytochrome c and caspase-9 in Huntington's disease (HD) patients and in a transgenic model of HD (R6/2 line). Neuronal cytochrome c immunoreactivity increased with neuropathological severity in HD patients. Concomitant with this finding, Western-blot analysis showed a shift in the distribution of cytochrome c from the mitochondrial to the cytosolic fraction with incremental cytosolic expression associated with greater striatal degeneration. Active caspase-9 immunoreactivity was present in both HD striatal neurons and in Western blots of severe-grade specimens. Similar findings were observed in the R6/2 mice. There was a temporal increase in expression and shift of cytochrome c from the mitochondrial to the cytosolic fraction from 4-13 wk of age. Activated caspase-9 and caspase 3 activities were present only at endstage disease. Although the present results provide evidence that key components of the intrinsic mitochondrial apoptotic pathway are activated in both HD patients and a transgene murine model of HD, these phenomena are prominent in only severe neuropathological grades in HD patients and HD mice, suggesting that apoptosis may play a greater role in neuronal death at endstage disease.
authors.affiliation: Geriatric Research Education and Clinical Center, Bedford VA Medical Center, MA 01730, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Kiechle
authors.forename: Alpaslan
authors.initials: A
authors.lastname: Dedeoglu
authors.forename: James
authors.initials: J
authors.lastname: Kubilus
authors.forename: Neil W
authors.initials: NW
authors.lastname: Kowall
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Robert M
authors.initials: RM
authors.lastname: Friedlander
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hersch
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
mesh_terms: D000367:Age Factors; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002451:Cell Compartmentation / Q000502:physiology; D003574:Cytochrome c Group / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology; D017072:Neostriatum / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology
chemical_list: D003574:Cytochrome c Group; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases