title: Adenosine A2A Receptors Modulate α-Synuclein Aggregation and Toxicity.
abstract: Abnormal accumulation of aggregated α-synuclein (aSyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and related synucleinopathies. Recent studies suggest a neuroprotective role of adenosine A2A receptor (A2AR) antagonists in PD. Nevertheless, the precise molecular mechanisms underlying this neuroprotection remain unclear. We assessed the impact of A2AR blockade or genetic deletion (A2AR KO) on synaptic plasticity and neuronal cell death induced by aSyn oligomers. We found that impairment of LTP associated with aSyn exposure was rescued in A2AR KO mice or upon A2AR blockade, through an NMDA receptor-dependent mechanism. The mechanisms underlying these effects were evaluated in SH-SY5Y cells overexpressing aSyn and rat primary neuronal cultures exposed to aSyn. Cell death in both conditions was prevented by selective A2AR antagonists. Interestingly, blockade of these receptors did not interfere with aSyn oligomerization but, instead, reduced the percentage of cells displaying aSyn inclusions. Altogether, our data raise the possibility that the well-documented effects of A2AR antagonists involve the control of the latter stages of aSyn aggregation, thereby preventing the associated neurotoxicity. These findings suggest that A2AR represent an important target for the development of effective drugs for the treatment of PD and related synucleinopathies.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa.|Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany.|Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto.|MedInUP, Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
authors.forename: Diana G
authors.initials: DG
authors.lastname: Ferreira
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa.
authors.forename: Vânia L
authors.initials: VL
authors.lastname: Batalha
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa.
authors.forename: Hugo
authors.initials: H
authors.lastname: Vicente Miranda
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa.
authors.forename: Joana E
authors.initials: JE
authors.lastname: Coelho
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa.|Faculty of Sciences, University of Lisbon, Lisbon, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Gomes
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra.
authors.forename: Francisco Q
authors.initials: FQ
authors.lastname: Gonçalves
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra.
authors.forename: Joana I
authors.initials: JI
authors.lastname: Real
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa.
authors.forename: José
authors.initials: J
authors.lastname: Rino
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto.|MedInUP, Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Albino-Teixeira
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra.|Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa.|Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa.
authors.forename: Luísa V
authors.initials: LV
authors.lastname: Lopes
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000633:toxicity; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D019706:Excitatory Postsynaptic Potentials; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D046509:Tissue Culture Techniques; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D011994:Recombinant Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; C497606:Snca protein, rat; D051844:alpha-Synuclein
keywords: Parkinson's disease; adenosine A2A receptors; hippocampus; neuroprotection; α-Synuclein