Superresolution Microscopy in Parkinson's Disease - Linking Mitochondrial Dysfunction and Alpha-Synuclein Misfolding

• Applicant: Dr. Janin Lautenschläger
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 275333484

Parkinsons disease (PD) is an age-related progressive neurodegenerative disease, characterized by prominent motor symptoms, caused by the substantial loss of dopaminergic neurons in a tiny region of the brain, the substantia nigra pars compacta. A hallmark of PD is the occurrence of so called Lewy bodies in patients brains, which are tightly packed aggregates of the protein alpha-synuclein. The aggregation and misfolding of alpha-synuclein plays an important role in the pathogenesis of PD and more and more it is recognized that early aggregates or even oligomers rather than the final inclusion bodies are mediating toxicity, however the mechanisms of alpha-synuclein aggregation are not sufficiently understood in the context of disease and no treatments currently exist. This project aims to explore a suspected link between alpha-synuclein aggregation and problems in the energy household. Thus we will focus on the energy demanding tracts of affected neurons, e.g. their axons, and synapses. We will exploit a range of cutting-edge imaging techniques that permit us to see protein aggregation as it takes place, with nanometer resolution directly in cell models of the disease. Using stochastic optical reconstruction microscopy (STORM) we will visualize the spatiotemporal aggregation pattern of alpha-synuclein, which will give us a first assertion on the initiation of protein aggregation. Furthermore, we will perform functional analyses, linking mitochondrial dysfunction and alpha-synuclein aggregation. Fluorescence lifetime imaging microscopy (FLIM) and stimulated emission depletion (STED) will allow us the live imaging of ATP supply, levels of calcium, and transmission of alpha-synuclein through the synapse during synaptic vesicle exocytosis. Exploring critical processes for the initiation of alpha-synuclein aggregation we hope to gain unique insights into the molecular processes of PD and thus to uncover targets for neuroprotective treatment strategies.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Dr. Clemens Kaminski