Troyan horses in the central nervous system: do extracellular vesicles govern neuroinflammation and alpha-synuclein propagation?

For 20 years, researchers and clinicians have been disentangling the critical role of -synuclein (aSYN) in protein aggregation and neuronal death in Parkinson’s disease (PD). More recently, they also discovered that aSYN mediates propagation of PD pathology across different brain regions, thereby leading to progressive worsening of the disease. The current project proposal is centered on the so-called ‘prion hypothesis’ of aSYN propagation and will investigate how toxic aSYN species propagate between neurons/brain regions, focusing on the role of innate immune cells and extracellular vesicles (EVs). EVs have emerged as important players in intercellular communication, that – by delivering their cargo from the donor to the acceptor cell – can modify the behavior of the acceptor cell. EVs appear to be the major vehicles for shuttling toxic proteins, such as aSYN, out of the cell and seeding protein aggregation in acceptor cells. In addition, they also play an important role in the propagation of the inflammatory response – which is believed to have a profound impact on disease progression – by facilitating communication between immune cells. In this project, I will focus on disentangling the role of EVs and neuroinflammation in aSYN propagation and design a unifying theory that reconciles the role of these two disease processes. Thus, the central research question is: “Do EVs add to the creation of an inflammatory micro-environment that modulates aSYN propagation?”