Genetic interaction between expanded murine Hdh alleles and p53 reveal deleterious effects of p53 on Huntington's disease pathogenesis.

Huntingtin, the protein product of the Huntington's disease (HD) gene, is known to interact with the tumor suppressor p53. It has recently been shown that activation of p53 upregulates the level of huntingtin, both in vitro and in vivo, whereas p53 deficiency in HD-transgenic flies and mice has been found to be beneficial. To explore further the involvement of p53 in HD pathogenesis, we generated mice homozygous for a mutant allele of Hdh (HdhQ140) and with zero, one, or two functional alleles of p53. p53 deficiency resulted in a reduction of mutant huntingtin expression in brain and testis, an increase in proenkephalin mRNA expression and a significant increase in nuclear aggregate formation in the striatum. Because aggregation of mutant huntingtin is suggested to be a protective mechanism, both the increase in aggregate load and the restoration of proenkephalin expression suggest a functional rescue of at least several aspects of the HD phenotype by a deficiency in p53.