查看文章

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. Using two mouse models of HD, we demonstrate that the urea cycle deficiency characterized by hyperammonemia, high blood citrulline and suppression of urea cycle enzymes is a prominent feature of HD. The resultant ammonia toxicity might exacerbate the neurological deficits of HD. Suppression of C/EBPα, a crucial transcription factor for the transcription of urea cycle enzymes, appears to mediate the urea cycle deficiency in HD. We found that in the presence of mutant Htt, C/EBPα loses its ability to interact with an important cofactor (CREB-binding protein). Moreover, mutant Htt recruited C/EBPα into aggregates, as well as suppressed expression of the C/EBPα gene. Consumption of protein-restricted diets not only led to the restoration of C/EBPα's activity …