Elucidating the role of the A2A adenosine receptor in neurodegeneration using neurons derived from Huntington's disease iPSCs.
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 of HD pathogenesis, 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 neuron-like 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.
Institute of Cellular and Organismic Biology, Academia Sinica.
Feng-Lan
FL
Chiu
Institute of Biomedical Sciences, Academia Sinica and.
Jun-Tasi
JT
Lin
Institute of Cellular and Organismic Biology, Academia Sinica, Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Ching-Yu
CY
Chuang
Institute of Biomedical Sciences, Academia Sinica and.
Ting
T
Chien
Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and College of Medicine, Chang-Gung University, Taoyuan, Taiwan and.
Chiung-Mei
CM
Chen
Department of Neurology, National Taiwan University Hospital (Hsinchu Branch), Hsinchu, Taiwan.
Kai-Hsiang
KH
Chen
Institute of Biomedical Sciences, Academia Sinica and.
Han-Yun
HY
Hsiao
Institute of Biomedical Sciences, Academia Sinica and.
Yow-Sien
YS
Lin
Institute of Biomedical Sciences, Academia Sinica and kuohuch@gate.sinica.edu.tw bmychern@ibms.sinica.edu.tw.
Yijuang
Y
Chern
Institute of Cellular and Organismic Biology, Academia Sinica, Genomics Research Center, Academia Sinica, Taipei, Taiwan, kuohuch@gate.sinica.edu.tw bmychern@ibms.sinica.edu.tw.
Hung-Chih
HC
Kuo
D000328:Adult; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004249:DNA Damage; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000096:biosynthesis; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D006861:Hydrogen Peroxide; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000235:genetics; D055495:Neurogenesis / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D055815:Young Adult
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; C497928:PPP1R1B protein, human; D043705:Receptor, Adenosine A2A; D006861:Hydrogen Peroxide; D017868:Cyclic AMP-Dependent Protein Kinases; D053148:Caspase 3