Wild-type huntingtin reduces the cellular toxicity of mutant huntingtin invivo

We have developed yeast artificial chromosome (YAC) transgenic mice express ing normal (YAC18) and mutant (YAC46 or YAC72) human huntingtin (htt), in a developmental- and tissue-specific manner, that is identical to endogenous htt. YAC72 mice develop selective degeneration of medium spiny projection neurons in the lateral striatum, similar to what is observed in Huntington disease. Mutant human htt expressed by YAC transgenes can compensate for th e absence of endogenous htt and can rescue the embryonic lethality that cha racterizes mice homozygous for targeted disruption of the endogenous Hdh ge ne (-/-). YAC72 mice lacking endogenous htt (YAC72 -/-) manifest a novel ph enotype characterized by infertility, testicular atrophy, aspermia, and mas sive apoptotic cell death in the testes. The testicular cell death in YAC72 -/- mice can be markedly reduced by increasing endogenous htt levels. YAC7 2 mice with equivalent levels of both wild-type and mutant htt (YAC72 +/+) breed normally and have no evidence of increased testicular cell death. Sim ilar findings are seen in YAC46 -/- mice compared with YAC46 +/+ mice, in w hich wild-type htt can completely counteract the proapoptotic effects of mu tant htt. YAC18 -/- mice display no evidence of increased cellular apoptosi s, even in the complete absence of endogenous htt, demonstrating that the m assive cellular apoptosis observed in YAC46 -/- mice and YAC72 -/- mice is polyglutamine-mediated toxicity from the mutant transgene. These data provi de the first direct in vivo evidence of a role for wild-type htt in decreas ing the cellular toxicity of mutant htt.