Human Molecular Genetics Advance Access originally published online on May 14, 2009
Human Molecular Genetics 2009 18(16):2929-2942; doi:10.1093/hmg/ddp230
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The A2A adenosine receptor rescues the urea cycle deficiency of Huntington's disease by enhancing the activity of the ubiquitin–proteasome system
1 Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei 115, Taiwan, Republic of China 2 Institute of Neuroscience and 3 Institute of Physiological and Anatomical Medicine, Tzu Chi University, Hualien 970, Taiwan, Republic of China 4 Department of Neurology, Chang Gung Memorial Hospital, Taipei, Taiwan, Republic of China 5 Department of Pediatrics, Medical Research and Medical Genetics, China Medical University Hospital, Taichung 404, Taiwan, Republic of China
* To whom correspondence should be addressed. Tel: +886 226523913; Fax: +886 227829143; Email: bmychern{at}ibms.sinica.edu.tw
Received January 28, 2009; Revised April 3, 2009; Accepted May 11, 2009
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The resultant mutant Htt protein (mHtt) forms aggregates in the brain and several peripheral tissues (e.g. the liver) and causes devastating neuronal degeneration. Metabolic defects resulting from Htt aggregates in peripheral tissues also contribute to HD pathogenesis. Simultaneous improvement of defects in both the CNS and peripheral tissues is thus the most effective therapeutic strategy and is highly desirable. We earlier showed that an agonist of the A2A adenosine receptor (A2A receptor), CGS21680 (CGS), attenuates neuronal symptoms of HD. We found herein that the A2A receptor also exists in the liver, and that CGS ameliorated the urea cycle deficiency by reducing mHtt aggregates in the liver. By suppressing aggregate formation, CGS slowed the hijacking of a crucial transcription factor (HSF1) and two protein chaperons (Hsp27 and Hsp70) into hepatic Htt aggregates. Moreover, the abnormally high levels of high-molecular-mass ubiquitin conjugates in the liver of an HD mouse model (R6/2) were also ameliorated by CGS. The protective effect of CGS against mHtt-induced aggregate formation was reproduced in two cells lines and was prevented by an antagonist of the A2A receptor and a protein kinase A (PKA) inhibitor. Most importantly, the mHtt-induced suppression of proteasome activity was also normalized by CGS through PKA. Our findings reveal a novel therapeutic pathway of A2A receptors in HD and further strengthen the concept that the A2A receptor can be a drug target in treating HD.