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

Study of membrane lipid composition and alpha-synuclein spreading

Neurodegenerative diseases (NDs), including Parkinson’s disease (PD), represent an escalating health and societal challenge with growing prevalence due to population aging. These disorders, characterized by progressive neuronal loss and the accumulation of misfolded proteins, impose a substantial economic and emotional burden on patients, families, and healthcare systems. Despite decades of research, disease-modifying therapies remain elusive, largely due to an incomplete understanding of the molecular mechanisms underlying neuronal dysfunction and protein aggregation. Lipids, as fundamental constituents of cellular membranes, are emerging as key modulators of protein aggregation, trafficking, and toxicity. Specific lipid species—such as phosphoinositides, sphingolipids, and oxysterols—regulate autophagy, lysosomal activity, and mitochondrial quality control, processes that are crucial for neuronal homeostasis. Alterations in lipid metabolism therefore profoundly affect the clearance of aggregation-prone proteins such as α-synuclein (aSyn), a central player in PD pathogenesis. Within this framework, the present MSCA project aimed to elucidate the contribution of a specific class of lipids, the N-acylphosphatidylethanolamines (NAPEs), to α-synuclein processing and spreading. NAPEs, normally a minor component of brain membranes, accumulate under pathological conditions, suggesting a potential role in disease-associated lipid remodeling. The project’s main objectives were to: (i) investigate how NAPEs influence aSyn intracellular localization and trafficking in neuronal cultures; (ii) determine their involvement in aSyn intercellular transfer in vitro; and (iii) characterize their effects in vivo using relevant animal models. By integrating advanced lipidomics, cell biology, and neurobiology approaches, this research provides novel mechanistic insights into the interplay between lipid metabolism and protein aggregation. Ultimately, the project contributes to the European priority of improving the understanding of brain function and dysfunction, laying the groundwork for future therapeutic strategies targeting lipid–protein interactions in PD and other neurodegenerative diseases.

Data: CORDIS, © European Union