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The A2A adenosine receptor rescues the UPS deficiency of Huntington's disease via a PKA‐dependent pathway
Author(s) -
Chern Yijuang,
Lin JiunTsai,
Lai HsingLin
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.lb55
Subject(s) - huntingtin , huntington's disease , adenosine a2a receptor , huntingtin protein , striatum , agonist , protein kinase a , g protein coupled receptor , genetically modified mouse , receptor , medium spiny neuron , signal transduction , adenosine , transgene , dopamine receptor d2 , pathogenesis , medicine , chemistry , biology , adenosine receptor , endocrinology , kinase , microbiology and biotechnology , dopamine , gene , disease , biochemistry
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion of the Huntingtin (HTT) gene. The normal Htt gene has 35 or fewer repeats in the N‐terminal region, while expansions of longer than 36 convert Htt into a toxic protein and evokes HD pathogenesis. Effective removal of mutant Htt has thus become one of the most challenging aspects of drug development for HD. The A2A adenosine receptor (A2AR) is a G protein‐coupled receptor that is expressed in many brain areas including the striatum. The main signal transduction activated by A2AR is the cAMP/protein kinase A (PKA)‐mediated pathway. We previously demonstrated that in an HD transgenic mouse model (R6/2), daily administration of CGS21680 (CGS), an agonist of A2AR, attenuated several major symptoms of HD. In the present study, we show that CGS ameliorated the impaired activity of the ubiquitin‐proteasome system (UPS) in striatal neurons and striatal synaptosome fractions of R6/2 mice. This function of CGS was blocked by an antagonist of A2AR and an inhibitor of protein kinase A (PKA), suggesting that it was mediated by A2AR in a PKA‐dependent manner. Our study collectively suggests that the UPS is a potential drug target for HD, and might have an important impact on the development of therapeutic interventions for HD.