Human Molecular Genetics Advance Access originally published online on January 9, 2007
Human Molecular Genetics 2007 16(5):483-498; doi:10.1093/hmg/ddl481
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Dysregulation of C/EBP
by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease
1 Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, Taiwan, 2 Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan, 3 Department of Neurology, Yang-Ming University School of Medicine and Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, 4 Department of Neurology, Chang Gung Memorial Hospital, Taipei, Taiwan, 5 Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan and 6 Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan
* To whom correspondence should be addressed. Tel: +886 226523913; Fax: +886 227829143; Email: bmychern{at}ibms.sinica.edu.tw
Received August 10, 2006; Revised December 26, 2006; Accepted December 28, 2006
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/EBP
, 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/EBP loses its ability to interact with an important cofactor (CREB-binding protein). Moreover, mutant Htt recruited C/EBP into aggregates, as well as suppressed expression of the C/EBP gene. Consumption of protein-restricted diets not only led to the restoration of C/EBP'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.
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