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 degeneration, as striatal vulnerability to excitotoxicity is increased by metabolic compromise. 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 mitochondrial 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 excitotoxins 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 dependent. We treated young, symptomatic R6/2 mice with 3-NP and found that despite their progressive neurological phenotype, they were not more susceptible to 3-NP intoxication than their WT littermates. Further, fewer R6/2 than WT mice developed striatal lesions. We suggest that compensatory mechanisms exist 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 expression of the genetic mutation.
Hickey
M A
MA
Department of Pharmacology, University of Cambridge, Cambridge, England.
Morton
A J
AJ
D000375:Aging; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003433:Crosses, Genetic; D003920:Diabetes Mellitus / Q000139:chemically induced; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004351:Drug Resistance / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics*; D007279:Injections, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009154:Mutation; D009574:Nitro Compounds; D011422:Propionates / Q000008:administration & dosage / Q000633:toxicity*; D013385:Succinate Dehydrogenase / Q000378:metabolism
D009574:Nitro Compounds; D011422:Propionates; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid