Breaking Bad - Phospholipase C Beta Disrupts Alpha-Synuclein Aggregation In Neuronal Cells

Alpha-synuclein (AS) is the main component of neurodegenerative plaques seen in Alzheimers and other diseases. There is evidence that oxidative stress promotes AS aggregation and plaque formation. Phospholipase Cβ1 (PLCβ1) transmits G proteins signals from hormones and neurotransmitters to induce the release of calcium from intracellular stores and subsequent activation of a host of calcium-sensitive enzymes. We have recently found that in neuronal cell lines, AS binds to PLCβ1, protecting it from calcium-regulated proteases that result in down-regulation of PLCβ1. In this study, we subjected neuronal cells to oxidative stress. This condition results in the down-regulation of many proteins, including PLCβ1. However, the levels of AS were unchanged under oxidative conditions. We postulated that the loss of PLCβ1 could promote aggregation of AS. In support of this idea, we found evidence that PLCβ1 prevents AS aggregation in vitro, and over-expression of PLCβ1 inhibits AS aggregation in live cells as indicated by live cell fluorescence imaging methods. Similarly, down-regulation of PLCβ1 promoted AS aggregation and preliminary studies suggest similar result for PLCβ1 down-regulation due to oxidation. We identified the interaction site between PLCβ1 and AS and are currently testing peptide inhibitors of AS aggregation based on their interaction. Our studies indicate that PLCβ1, or possibly other AS binding partners, might reduce damage by AS aggregation under basal or oxidative stress conditions. This work was supported by NIH GM053132.