LipiSyn · Study of membrane lipid composition and alpha-synuclein spreading

Neurodegenerative pathologies (NDs), including Parkinson’s disease, represent a huge burden worldwide from a health, economical and societal point of view. However, the physiopathology of these diseases is not well understood, making the discovery of a cure extremely hard. A common feature of NDs is the accumulation of misfolded proteins such as alpha-synuclein (asyn) in different types of proteinaceous aggregates, the formation of which follows a prion-like spreading mechanism. In this context, the host lab has extensively studied the capability of neuronal and non-neuronal cells to transfer asyn through Tunneling Nano Tubes (TNTs). However, the causes and mechanisms of a asyn misfolding and accumulation are still poorly understood. Asyn is a lipid-binding protein, that associates with the head of phospholipids, and it is involved in the regulation of vesicles trafficking. Given the ability of asyn to directly bind membranes, studying the lipid composition of asyn-interacting membranes appears to be pivotal to understand its function and the consequences of its misfolding on the cell homeostasis and metabolism. In this regard, a peculiar class of glycerophospholipids, called N-acylethanolamines (NAPEs), which are enriched in the neuronal membranes after injurious stimuli, have been shown to regulate the binding and stabilization of proteins that interact with the inner leaflet. The present proposal aims to investigate the role of NAPEs in asyn anchorage to membrane, and how the perturbation of membrane lipid composition is affecting asyn spreading in vitro and in vivo. The combination of pharmacological, biochemical and molecular biology techniques applied in various neurodegenerative models and my strong knowledge in NAPE biology and metabolism, together with the expertise of the host lab in cutting-edge imaging techniques applied to membrane trafficking and asyn spreading are crucial and will assure the successful development of this project.