Heterotypic Droplet Formation by Pro-Inflammatory S100A9 and Neurodegenerative Disease-Related α-Synuclein

Liquid-liquid phase separation of proteins and nucleic acids is a rapidly emerging field of study, aimed at understanding the process of biomolecular condensate formation. Recently, it has been discovered that different neurodegenerative disease-related proteins, such as α-synuclein and amyloid-β are capable of forming heterotypic droplets. Other reports have also shown non-LLPS cross-interactions between various amyloidogenic proteins and the resulting influence on their amyloid fibril formation. This includes the new discovery of pro-inflammatory S100A9 affecting the aggregation of both amyloid-β, as well as α-synuclein. In this study, we explore the formation of heterotypic droplets by S100A9 and α-synuclein. We show that their mixture is capable of assembling into both homotypic and heterotypic condensates and that this cross-interaction alters the aggregation mechanism of α-synuclein. These results provide insight into the influence of S100A9 on the process of neurodegenerative disease-related protein LLPS and aggregation.