Dysregulation of C/EBPalpha by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease.
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/EBPalpha, 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/EBPalpha loses its ability to interact with an important cofactor (CREB-binding protein). Moreover, mutant Htt recruited C/EBPalpha into aggregates, as well as suppressed expression of the C/EBPalpha gene. Consumption of protein-restricted diets not only led to the restoration of C/EBPalpha's activity, and repair of the urea cycle deficiency and hyperammonemia, but also ameliorated the formation of Htt aggregates, the motor deterioration, the suppression of striatal brain-derived neurotrophic factor and the normalization of three protein chaperones (Hsp27, Hsp70 and Hsp90). Treatments aimed at repairing the urea cycle deficiency may provide a new strategy for dealing with HD.
Chiang
Ming-Chang
MC
Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, Taiwan.
Chen
Hui-Mei
HM
Lee
Yi-Hsin
YH
Chang
Hao-Hung
HH
Wu
Yi-Chih
YC
Soong
Bing-Wen
BW
Chen
Chiung-Mei
CM
Wu
Yih-Ru
YR
Liu
Chin-San
CS
Niu
Dau-Ming
DM
Wu
Jer-Yuarn
JY
Chen
Yuan-Tsong
YT
Chern
Yijuang
Y
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D002956:Citrulline / Q000097:blood; D004032:Diet; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009043:Motor Activity; D050505:Mutant Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D014508:Urea / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D022763:CCAAT-Enhancer-Binding Protein-alpha; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D002956:Citrulline; D014508:Urea