Skip Navigation


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
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
16/5/483    most recent
ddl481v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Chiang, M.-C.
Right arrow Articles by Chern, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chiang, M.-C.
Right arrow Articles by Chern, Y.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dysregulation of C/EBP{alpha} by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease

Ming-Chang Chiang1,2, Hui-Mei Chen1, Yi-Hsin Lee1, Hao-Hung Chang1, Yi-Chih Wu1, Bing-Wen Soong3, Chiung-Mei Chen4, Yih-Ru Wu4, Chin-San Liu5, Dau-Ming Niu6, Jer-Yuarn Wu1, Yuan-Tsong Chen1 and Yijuang Chern1,2,*

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{alpha}, 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{alpha} loses its ability to interact with an important cofactor (CREB-binding protein). Moreover, mutant Htt recruited C/EBP{alpha} into aggregates, as well as suppressed expression of the C/EBP{alpha} gene. Consumption of protein-restricted diets not only led to the restoration of C/EBP{alpha}'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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Neurosci.Home page
S.-Y. Chou, J.-Y. Weng, H.-L. Lai, F. Liao, S. H. Sun, P.-H. Tu, D. W. Dickson, and Y. Chern
Expanded-Polyglutamine Huntingtin Protein Suppresses the Secretion and Production of a Chemokine (CCL5/RANTES) by Astrocytes
J. Neurosci., March 26, 2008; 28(13): 3277 - 3290.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.