Elucidating the role of the A2A adenosine receptor in neurodegeneration using neurons derived from Huntington's disease iPSCs
Journal
Human Molecular Genetics
Journal Volume
24
Journal Issue
21
Pages
6066-6079
Date Issued
2015
Author(s)
Abstract
Huntington's disease (HD) is an autosomal-dominant degenerative disease caused by a cytosine-adenine-guanine trinucleotide expansion in the Huntingtin (htt) gene. The most vulnerable brain areas to mutant HTT-evoked toxicity are the striatum and cortex. In spite of the extensive efforts that have been devoted to the characterization ofHDpathogenesis, no disease-modifying therapy for HD is currently available. The A2A adenosine receptor (A2AR) is widely distributed in the brain, with the highest level observed in the striatum. We previously reported that stimulation of the A2AR triggers an anti-apoptotic effect in a rat neuronlike cell line (PC12). Using a transgenic mouse model (R6/2) of HD, we demonstrated that A2AR-selective agonists effectively ameliorate several major symptoms of HD. In the present study, we show that human iPSCs can be successfully induced to differentiate into DARPP32-positive, GABAergic neurons which express the A2AR in a similar manner to striatal medium spiny neurons. When compared with those derived from control subjects (CON-iPSCs), these HD-iPSC-derived neurons exhibited a higher DNA damage response, based on the observed expression of γH2AX and elevated oxidative stress. This is a critical observation, because oxidative damage and abnormal DNA damage/repair have been reported in HD patients. Most importantly, stimulation of the A2AR using selective agonists reduced DNA damage and oxidative stress-induced apoptosis in HD-iPSC-derived neurons through a cAMP/PKA-dependent pathway. These findings support our hypothesis that human neurons derived from diseased iPSCs might serve as an important platform to investigate the beneficial effects and underlying mechanisms of A2AR drugs. ? The Author 2015.
SDGs
Other Subjects
4 aminobutyric acid receptor; adenosine A2 receptor; 4 aminobutyric acid receptor; adenosine A2a receptor; caspase 3; cyclic AMP dependent protein kinase; HTT protein, human; hydrogen peroxide; nerve protein; phosphoprotein DARPP 32; PPP1R1B protein, human; animal cell; animal experiment; animal model; apoptosis; Article; cell differentiation; controlled study; corpus striatum; DNA damage; human; human cell; Huntington chorea; mouse; nerve cell; nerve degeneration; nonhuman; oxidative stress; priority journal; protein expression; adult; biosynthesis; cell culture; cell line; female; genetics; Huntington chorea; male; metabolism; middle aged; nervous system development; newborn; pathology; pluripotent stem cell; young adult; Adult; Apoptosis; Caspase 3; Cell Line; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; DNA Damage; Dopamine and cAMP-Regulated Phosphoprotein 32; Female; GABAergic Neurons; Humans; Huntington Disease; Hydrogen Peroxide; Infant, Newborn; Male; Middle Aged; Nerve Degeneration; Nerve Tissue Proteins; Neurogenesis; Pluripotent Stem Cells; Receptor, Adenosine A2A; Young Adult
Type
journal article