title: Suppression of adenosine 2a receptor (A2aR)-mediated adenosine signaling improves disease phenotypes in a mouse model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease in which the majority of upper and lower motor neurons are degenerated. Despite intensive efforts to identify drug targets and develop neuroprotective strategies, effective therapeutics for ALS remains unavailable. The identification and characterization of novel targets and pathways remain crucial in the development of ALS therapeutics. Adenosine is a major neuromodulator that actively regulates synaptic transmission. Interestingly, adenosine levels are significantly elevated in the cerebrospinal fluid (CSF) of progressing human ALS patients. In the current study, we showed that adenosine 2a receptor (A2aR), but not adenosine 1 receptor (A1R), is highly enriched in spinal (motor) neurons. A2aR expression is also selectively increased at the symptomatic onset in the spinal cords of SOD1G93A mice and end-stage human ALS spinal cords. Interestingly, we found that direct adenosine treatment is sufficient to induce embryonic stem cell-derived motor neuron (ESMN) cell death in cultures. Subsequent pharmacological inhibition and partial genetic ablation of A2aR (A2aR(+/-)) significantly protect ESMN from SOD1G93A(+) astrocyte-induced cell death and delay disease progression of SOD1G93A mice. Taken together, our results provide compelling novel evidence that A2aR-mediated adenosine signaling contributes to the selective spinal motor neuron degeneration observed in the SOD1G93A mouse model of ALS.
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USA.
authors.forename: Seng Kah
authors.initials: SK
authors.lastname: Ng
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USA.
authors.forename: Haruki
authors.initials: H
authors.lastname: Higashimori
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USA; Neuroscience Program, Tufts Sackler School of Graduate Biomedical Sciences, 136 Harrison Ave, Boston, MA 02111, USA.
authors.forename: Michaela
authors.initials: M
authors.lastname: Tolman
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USA; Neuroscience Program, Tufts Sackler School of Graduate Biomedical Sciences, 136 Harrison Ave, Boston, MA 02111, USA. Electronic address: yongjie.yang@tufts.edu.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000241:Adenosine / Q000378:metabolism* / Q000627:therapeutic use; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D053580:Muscle Strength / Q000187:drug effects / Q000235:genetics; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D043705:Receptor, Adenosine A2A / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D056892:Mediator Complex; D011687:Purines; D043705:Receptor, Adenosine A2A; C111599:istradefylline; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D000241:Adenosine
keywords: A(2a) receptor; Adenosine; Amyotrophic lateral sclerosis (ALS); Astrocyte; KW6002; Motor neuron