title: Early degenerative changes in transgenic mice expressing mutant huntingtin involve dendritic abnormalities but no impairment of mitochondrial energy production.
abstract: Mitochondrial defects, which occur in the brain of late-stage Huntington's disease (HD) patients, have been proposed to underlie the selective neuronal loss in the disease. To shed light on the possible role of mitochondrial energy impairment in the early phases of HD pathophysiology, we carried out Golgi impregnation and quantitative histochemical/biochemical studies in HD full-length cDNA transgenic mice that were symptomatic but had not developed to a stage in which neuronal loss could be documented. Golgi staining showed morphologic abnormalities that included a significant decrease in the number of dendritic spines and a thickening of proximal dendrites in striatal and cortical neurons. In contrast, measurements of mitochondrial electron transport Complexes I-IV did not reveal changes in the striatum and cerebral cortex in these mice. Examination of the neostriatum and cerebral cortex in human presymptomatic and pathological Grade 1 HD cases also showed no change in the activity of mitochondrial Complexes I-IV. These data suggest that dendritic alterations precede irreversible cell loss in HD, and that mitochondrial energy impairment is a consequence, rather than a cause, of early neuropathological changes.
authors.affiliation: National Human Genome Research Institute, NIH, 49 Convent Drive, Bethesda, MD 20892, USA.
authors.forename: P
authors.initials: P
authors.lastname: Guidetti
authors.forename: V
authors.initials: V
authors.lastname: Charles
authors.forename: E Y
authors.initials: EY
authors.lastname: Chen
authors.forename: P H
authors.initials: PH
authors.lastname: Reddy
authors.forename: J H
authors.initials: JH
authors.lastname: Kordower
authors.forename: W O
authors.initials: WO
authors.lastname: Whetsell
authors.forename: R
authors.initials: R
authors.lastname: Schwarcz
authors.forename: D A
authors.initials: DA
authors.lastname: Tagle
mesh_terms: D000818:Animals; D002421:Caudate Nucleus / Q000473:pathology; D004396:Coloring Agents; D003342:Corpus Striatum / Q000473:pathology*; D018076:DNA, Complementary; D003712:Dendrites / Q000473:pathology* / Q000648:ultrastructure; D004734:Energy Metabolism; D007839:Functional Laterality; D006056:Golgi Apparatus / Q000473:pathology / Q000648:ultrastructure; D006579:Heterozygote; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009043:Motor Activity; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D011699:Putamen / Q000473:pathology; D013003:Somatosensory Cortex / Q000378:metabolism* / Q000473:pathology
chemical_list: D004396:Coloring Agents; D018076:DNA, Complementary; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins