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Adenosine A2A Receptors Modulate α-Synuclein Aggregation and Toxicity

Lookup NU author(s): Professor Tiago OuteiroORCiD


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© The Author 2015. Published by Oxford University Press. All rights reserved.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.

Publication metadata

Author(s): Ferreira DG, Batalha VL, Miranda HV, Coelho JE, Gomes R, Goncalves FQ, Real JI, Rino J, Albino-Teixeira A, Cunha RA, Outeiro TF, Lopes LV

Publication type: Article

Publication status: Published

Journal: Cerebral Cortex

Year: 2017

Volume: 27

Issue: 1

Pages: 718-730

Print publication date: 01/01/2017

Online publication date: 03/11/2015

Acceptance date: 01/01/1900

ISSN (print): 1047-3211

ISSN (electronic): 1460-2199

Publisher: Oxford University Press


DOI: 10.1093/cercor/bhv268


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