Mice transgenic for the Huntington's disease mutation are resistant to chronic 3-nitropropionic acid-induced striatal toxicity

Neuronal loss in Huntington's disease (HD) is seen first in the neostriatum . It has been suggested that impaired metabolism underlies this degeneratio n, as striatal vulnerability to excitotoxicity is increased by metabolic co mpromise. At 12 weeks of age, a transgenic mouse carrying the HD mutation ( R6/2 line) has been shown to have an increased vulnerability to the mitocho ndrial toxin 3-nitropropionic acid (3-NP). However, in contrast, younger R6 /2 mice appear to be less vulnerable than wild-type (WT) mice to the excito toxins kainic acid and quinolinic acid (QA). In this study, we examine the possibility that the sensitivity of R6/2 mice to 3-NP might be age dependen t. We treated young, symptomatic R6/2 mice with 3-NP and found that despite their progressive neurological phenotype, they were not more susceptible t o 3-NP intoxication than their WT littermates. Further, fewer R6/2 than WT mice developed striatal lesions. We suggest that compensatory mechanisms ex ist in the R6/2 mouse brain that protect it against the toxic effect of the transgene and coincidentally protect against exogenous toxins such as 3-NP , QA, and kainic acid. The existence of similar compensatory mechanisms may explain why, in humans, HD is a late-onset disorder, despite early express ion of the genetic mutation.