Adenosine A_2AReceptors 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.

Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

“…This view collaborates with two recent studies that A 2A R antagonists decreased the percentage of cells displaying α-Syn inclusions in cultured cells (Ferreira et al, 2015) and that caffeine (nonselective adenosine antagonist) attenuates toxicity of α-Syn aggregates in vitro and in a yeast proteotoxicity model of PD (Kardani and Roy, 2015). Phosphorylation of α-Syn at Ser129 might have strong connections with Lewy bodies' generation and even the dopaminergic neurodegeneration (Fujiwara et al, 2002).…”

“…Abnormal activation of A 2A R might lead to over-activation of NMDA receptor, which is a prominent synaptic event resulting in excitotoxicity (Besancon et al, 2008). This notion is supported by a recent study showing that A 2A R blockade rescues SH-SY5Y cell toxicity induced by endogenous α-Syn via NMDA receptor (Ferreira et al, 2015). Notably, in primary hippocampal culture, glutamatergic neurons are more sensitive than the GABAergic neurons to the addition of preformed α-Syn and its aggregation and toxicity due to their higher level of α-Syn expression despite comparable capacity of two neuronal populations to internalize α-Syn (Taguchi et al, 2014).…”

“…PD patients show a noted safety profile (Chen et al, 2013). Further investigation into interplay between G protein-coupled receptors and pathological accumulated proteins, including Aβ (Canas et al, 2009b;Dall'Igna et al, 2007;Orr et al, 2015), α-Syn (Ferreira et al, 2015), Tau (Laurent et al, 2016) and ataxin-3 (Goncalves et al, 2013), may offer new therapeutic opportunities for controlling protein aggregation, neurodegeneration and cognitive impairments. WT and A 2A R KO mice were bilaterally injected with PBS or A53T α-Syn fibrils into DG and analyzed for working memory and locomotor activity at two months after the injection.…”

“…This working hypothesis is based on two lines of experimental evidence: first, recent studies suggest a requisite facilitative role of the A 2A R in α-Syn pathology since A 2A R blockade decreases the number of α-Syn aggregates in cultured cells and reverses synaptic dysfunction in brain slices (Ferreira et al, 2015); also genetic inactivation of the A 2A R reduces dopaminergic neurodegeneration induced by over-expressing WT α-Syn in tyrosinehydroxylase-positive neurons (Kachroo and Schwarzschild, 2012). Second, many studies including ours have shown that A 2A R inactivation not only enhances working memory (Wei et al, 2011;Zhou et al, 2009), reversal learning (Wei et al, 2011), goal-directed behavior (Yu et al, 2009) and Pavlovian fear conditioning (Wei et al, 2014) in normal animals, but also reverses working memory impairments in animal models of PD (Kadowaki Horita et al, 2013), Alzheimer's disease (AD) (Canas et al, 2009b;Dall'Igna et al, 2007) and Huntington's disease (HD) (Li et al 2015b).…”

α‐Synuclein Oligomers: A Study in Diversity

“…This damage was marked by the loss of synaptic markers, such as synaptophysin, synapsin‐1, and vesicle‐associated membrane protein‐1 (VAMP‐1) . Moreover, extracellular unmodified‐ and HNE‐αSOs, but not monomers or fibrils, were able to modulate synaptic transmission and impair LTP, most likely via NMDA receptor activation . LTP is the chemical process in synapses that underlies synaptic plasticity, which is important for learning and memory, and it is reduced in PD animal models .…”