Adenosine A(2A) Receptors Modulate alpha-Synuclein Aggregation and Toxicity

• Type: Article in International Scientific Journal
• Date: 2017

Authors

Ferreira, DG (Author) Other; Batalha, VL (Author) Other; Vicente Miranda, H (Author) Other; Coelho, JE (Author) Other; Gomes, R (Author) Other; Goncalves, FQ (Author) Other; Real, JI (Author) Other; Rino, J (Author) Other; Albino Teixeira, A (Author) FMUP; Cunha, RA (Author) Other; Outeiro, TF (Author) Other; Lopes, LV (Author) Other

Journal

Title: Cerebral Cortex

Vol. 27

Pages: 718-730

ISSN: 1047-3211

Publisher: Oxford University Press

Indexing

ISI Web of Knowledge - 46 Citations

Scopus - 42 Citations

Other information

Authenticus ID: P-00M-HWS

DOI: 10.1093/cercor/bhv268

Abstract (EN): Abnormal accumulation of aggregated alpha-synuclein (aSyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and related synucleinopathies. Recent studies suggest a neuroprotective role of adenosine A(2A) receptor (A(2A)R) antagonists in PD. Nevertheless, the precise molecular mechanisms underlying this neuroprotection remain unclear. We assessed the impact of A(2A)R blockade or genetic deletion (A(2A)R KO) on synaptic plasticity and neuronal cell death induced by aSyn oligomers. We found that impairment of LTP associated with aSyn exposurewas rescued in A(2A)R KO mice or upon A(2A)R 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 A(2A)R 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 A(2A)R antagonists involve the control of the latter stages of aSyn aggregation, thereby preventing the associated neurotoxicity. These findings suggest that A(2A)R represent an important target for the development of effective drugs for the treatment of PD and related synucleinopathies.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13