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.