title: The A2A adenosine receptor rescues the urea cycle deficiency of Huntington's disease by enhancing the activity of the ubiquitin-proteasome system.
abstract: 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 A(2A) adenosine receptor (A(2A) receptor), CGS21680 (CGS), attenuates neuronal symptoms of HD. We found herein that the A(2A) 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 A(2A) 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 A(2A) receptors in HD and further strengthen the concept that the A(2A) receptor can be a drug target in treating HD.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei 115, Taiwan, Republic of China.
authors.forename: Ming-Chang
authors.initials: MC
authors.lastname: Chiang
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Chen
authors.forename: Hsing-Lin
authors.initials: HL
authors.lastname: Lai
authors.forename: Hsiao-Wen
authors.initials: HW
authors.lastname: Chen
authors.forename: Szu-Yi
authors.initials: SY
authors.lastname: Chou
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010627:Phenethylamines / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D014508:Urea / Q000378:metabolism*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D025801:Ubiquitin; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D014508:Urea; D046988:Proteasome Endopeptidase Complex; D000241:Adenosine