Early degenerative changes in transgenic mice expressing mutant huntingtininvolve dendritic abnormalities but no impairment of mitochondrial energy production

Mitochondrial defects, which occur in the brain of late-stage Huntington's disease (HD) patients, have been proposed to underlie the selective neurona l 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 H D full-length cDNA transgenic mice that were symptomatic but had not develo ped to a stage in which neuronal loss could be documented. Golgi staining s howed morphologic abnormalities that included a significant decrease in the number of dendritic spines and a thickening of proximal dendrites in stria tal and cortical nenrons, In contrast, measurements of mitochondrial electr on transport Complexes I-IV did not reveal changes in the striatum and cere bral cortex in these mice. Examination of the neostriatum and cerebral cort ex in human presymptomatic and pathological Grade I 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 e arly neuropathological changes. (C) 2001 Academic Press.