In-cell NMR monitoring of alpha-Synuclein aggregation in neuronal cells
European Commission Horizon 2020
Neurodegenerative disease in general
Intracellular aggregation of the human amyloid protein alpha-synuclein is causally involved in Parkinsons disease, a debilitating neurodegenerative disorder. The goal of this project is to combine low-resolution, fluorescence-imaging methods with high-resolution in-cell NMR and EPR spectroscopy techniques to derive macroscopic and microscopic insights into alpha-synuclein aggregate structures directly in neuronal cells. To achieve this goal, we will employ different sets of cultured neurons and investigate intracellular alpha-synuclein aggregation under defined conditions of mitochondrial dysfunction and cellular oxidative stress, two of the most common denominators of the disease. Importantly, we will also establish a human stem cell model for studying alpha-synuclein aggregation with high-resolution in-cell NMR and EPR methods, by using induced pluripotent stem cell (iPSC) derived dopaminergic neurons from Parkinsons disease patients and control individuals. Results from this study will provide novel insights into the native mechanisms of intracellular aggregate formation and ultimately enable novel pharmacological approaches for therapeutic intervention.