Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse

Huntington's disease is a progressive neurodegenerative disease caused by a n abnormally expanded (>36) CAG repeat within the ITI5 gene encoding a wide ly expressed 349-kd protein, huntingtin. The medium spiny neurons of the ca udate preferentially degenerate in Huntington's disease, with the presence of neuronal intranuclear inclusions. Excitotoxicity is thought to be import ant in the pathogenesis of Huntington's disease; the recently described mit ochondrial respiratory chain and aconitase defects in Huntington's disease brain are consistent with this hypothesis. A transgenic mouse model (R6/2) of Huntington's disease develops a movement disorder, muscle wasting, and p remature death at about 14 to 16 weeks. Selective neuronal death in these m ice is not seen until 14 weeks. Biochemical analysis of R6/2 mouse brain at 12 weeks demonstrated a significant reduction in aconitase and mitochondri al complex IV activities in the striatum and a decrease in complex IV activ ity in the cerebral cortex. Increased immunostaining for inducible nitric o xide synthase and nitrotyrosine was seen in the transgenic mouse model but not control mouse brains. These results extend the parallels between Huntin gton's disease and the transgenic mouse model to biochemical events and sug gest complex IV deficiency and elevated nitric oxide and superoxide radical generation precede neuronal death in the R6/2 mouse and contribute to path ogenesis.