Mice transgenic for exon 1 of the Huntington's disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6-hydroxydopamine

Huntington's disease is an autosomal dominant hereditary neurodegenerative disorder characterized by severe striatal cell loss. Dopamine (DA) has been suggested to play a role in the pathogenesis of the disease. We have previ ously reported that transgenic mice expressing exon 1 of the human Huntingt on gene (R6 lines) are resistant to quinolinic acid-induced striatal toxici ty. In this study we show that with increasing age, R6/1 and R6/2 mice deve lop partial resistance to DA- and 6-hydroxydopamine-mediated toxicity in th e striatum. Using electron microscopy, we found that the resistance is loca lized to the cell bodies and not to the neuropil. The reduction of dopamine and cAMP regulated phosphoprotein of a molecular weight of 32 kDa (DARPP-3 2) in R6/2 mice does not provide the resistance, as DA-Induced striatal les ions are not reduced in size in DARPP-32 knockout mice. Neither DA receptor antagonists nor a N-methyl-D-aspartate (NMDA) receptor blocker reduce the size of DA-induced striatal lesions, suggesting that DA toxicity is not dep endent upon DA- or NMDA receptor-mediated pathways. Moreover, superoxide di smutase-1 overexpression, monoamine oxidase inhibition and the treatment wi th the free radical scavenging spin-trap agent phenyl-butyl-tert-nitrone (P BN) also did not block DA toxicity. Levels of the antioxidant molecules, gl utathione and ascorbate were not increased in R6/1 mice, Because damage to striatal neurons following intrastriatal injection of 6-hydroxydopamine was also reduced in R6 mice, a yet-to-be identified antioxidant mechanism may provide neuroprotection in these animals. We conclude that striatal neurons of R6 mice develop resistance to DA-induced toxicity with age.