The A2A adenosine receptor rescues the urea cycle deficiency of Huntington's disease by enhancing the activity of the ubiquitin-proteasome system

Ming Chang Chiang, Hui Mei Chen, Hsing Lin Lai, Hsiao Wen Chen, Szu Yi Chou, Chiung Mei Chen, Fuu Jen Tsai, Yijuang Chern

Research output: Contribution to journalArticle

56 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)2929-2942
Number of pages14
JournalHuman Molecular Genetics
Volume18
Issue number16
DOIs
Publication statusPublished - 2009
Externally publishedYes

Fingerprint

Adenosine A2A Receptors
Deficiency Diseases
Huntington Disease
Proteasome Endopeptidase Complex
Ubiquitin
Urea
Mutant Proteins
Liver
Cyclic AMP-Dependent Protein Kinases
Adenosine A2 Receptor Agonists
Adenosine A2 Receptor Antagonists
Protein Kinase Inhibitors
Neurodegenerative Diseases
2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
Liver Diseases
Transcription Factors
Cell Line
Brain
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

The A2A adenosine receptor rescues the urea cycle deficiency of Huntington's disease by enhancing the activity of the ubiquitin-proteasome system. / Chiang, Ming Chang; Chen, Hui Mei; Lai, Hsing Lin; Chen, Hsiao Wen; Chou, Szu Yi; Chen, Chiung Mei; Tsai, Fuu Jen; Chern, Yijuang.

In: Human Molecular Genetics, Vol. 18, No. 16, 2009, p. 2929-2942.

Research output: Contribution to journalArticle

Chiang, Ming Chang ; Chen, Hui Mei ; Lai, Hsing Lin ; Chen, Hsiao Wen ; Chou, Szu Yi ; Chen, Chiung Mei ; Tsai, Fuu Jen ; Chern, Yijuang. / The A2A adenosine receptor rescues the urea cycle deficiency of Huntington's disease by enhancing the activity of the ubiquitin-proteasome system. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 16. pp. 2929-2942.
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