Understanding Caffeine’s Role in Attenuating the Toxicity of α-Synuclein Aggregates: Implications for Risk of Parkinson’s Disease

Abstract

Epidemiological studies report a beneficial relationship between drinking coffee and the risk of developing Parkinson's disease (PD). This is likely due to caffeine, a constituent of coffee, acting as an adenosine A2A receptor antagonist. This study was planned to investigate whether caffeine has any effect on the aggregation of α-synuclein, present in Lewy bodies, the pathological hallmark of PD, which may account for this positive association. Aggregation of recombinant α-synuclein was followed in vitro and in a well-validated yeast proteotoxicity model of PD. Caffeine was found to have twin effects: it accelerated the process of aggregation and also altered the nature of mature aggregates. Aggregates formed in the presence of caffeine displayed amorphous as well as fibrillar morphology. In the presence of caffeine, the toxicity of oligomers and aggregates was diminished, with concomitant reduction in intracellular oxidative stress, decreased oxidative proteome damage, and increased cell survival. Caffeine-treated samples showed improved binding to phospholipids, a property likely to be important in cellular functioning of α-synuclein. Far-UV CD spectroscopy and fluorescence quenching analysis revealed that caffeine induced transient changes in this intrinsically disordered protein, forming a non-native species that enhanced the rate of aggregation of α-synuclein and modified the population of mature aggregates, introducing a higher fraction of amorphous, less toxic species. Increasingly, it is felt that the process of fibrillation itself, along with the nature of mature aggregates, dictates the cytotoxicity of the process. Our results provide a rationale for the observed epidemiological link between drinking coffee and developing PD.

Phenylindanes in Brewed Coffee Inhibit Amyloid-Beta and Tau Aggregation

“…Caffeine ( 1 ) also failed to inhibit the oligomerization of α-synuclein, and no pro-aggregation effect was observed ( Table 3 ). This result is consistent with a previous report on the fibrillization of α-synuclein in the presence of caffeine ( 1 ) ( Kardani and Roy, 2015 ): fibrils grown in the presence of caffeine ( 1 ) showed different morphology relative to fibrils grown in its absence, but the authors claim that this was not due to an interaction of caffeine ( 1 ) with the α-synuclein protein. The lack of an observable interaction between caffeine ( 1 ) and Aβ/tau/α-synuclein would suggest that the observed activity of the coffee extracts is not due to the caffeine component.…”

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).…”

High-Throughput Screening Methodology to Identify Alpha-Synuclein Aggregation Inhibitors

“…Chemical kinetics approaches would allow the quantitative detection of the effects of potential therapeutic molecules on aggregation [21]; however, the application of this type of analysis is hampered by the low reproducibility of aggregation reactions, resulting in dissimilar kinetic parameters and/or high errors even within replicates in the same aggregation assay. This is especially true for α-syn, a protein displaying a very slow aggregation reaction, usually taking several days, which is highly influenced by factors like pH, temperature, agitation or the presence of impurities [18,19,20,22,23,24,25,26,27,28,29,30,31]. The lack of reproducibility between aggregation curves is a strong limitation to identify bona fide aggregation inhibitors, since their potency becomes hidden in overlapping errors bars, especially at the beginning of the reaction, where the more toxic oligomeric species are expected to be formed.…”