Cryo-EM and the Nano-World of Parkinson's Disease

Cryo-electron microscopy is revolutionizing structural biology. The high-resolution structures of soluble and membrane proteins, or larger complexes of such proteins, can be determined at high efficiency, as will be demonstrated from recent examples on ion channels and multi-drug resistance membrane proteins. Current limitations of cryo-EM will be outlined, and approaches to advance cryo-EM with respect to resolution, minimal sample size, or structure determination efficiency, will be discussed. The application of microfluidic technology, as well as novel electron microscopy data collection schemes and data processing workflows will be discussed.
Parkinson’s disease (PD) is a neurodegenerative disease of multifactorial origins. So far, available treatments only affect symptoms. The molecular causes or cellular mechanisms in PD are not understood, reliable diagnosis in patients is difficult, and no treatment is available to slow down or prevent progression of the disease. The protein alpha-synuclein is a prime suspect for the cause of Parkinson’s disease. This soluble protein is capable of aggregating into prionoid fibrils in a variety of conformational strains. The structural analysis of these via cryo-EM will be presented, and high-resolution structures of different alpha-synuclein fibril strains from wild-type, as well as post-translationally modified, truncated, or PD-relevant mutation carrying protein will be presented and discussed.  In parallel, electron microscopy studies of post-mortem human brain from Parkinson’s disease tissue donors with a post-mortem delay of only 3 hours will be presented, and the ultrastructure of Lewy body plaques in the brain tissue, which are highly enriched in the protein alpha-synuclein, will be discussed. These studies have implications for our understanding of the possible causes and mechanisms of Parkinson’s disease.

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Henning Stahlberg Bio
Henning Stahlberg studied Physics at the Technical University of Berlin, and obtained his PhD from the EPFL Lausanne in 1997 in Structural Biology (Groups Prof. Horst Vogel and Prof. Jacques Dubochet). He then obtained his Habilitation in the group of Prof. Andreas Engel at the Biozentrum of the University of Basel in 2002, and accepted in 2003 a faculty position in Molecular and Cell Biology at the University of California in Davis, CA, USA, where he established a laboratory for high-resolution structure determination of biological macromolecules by cryo-transmission electron microscopy.  Since 2009, Stahlberg is Professor and director of the Center for Cellular Imaging and NanoAnalytics (C-CINA) of the Biozentrum at the University of Basel.
The Stahlberg group is focusing on Parkinson's Disease and on Membrane Protein Structures. The main method is cryo-electron microscopy, which is extended by multidisciplinary approaches, including use of neuronal cell cultures and human brain tissue, using expression and purification of relevant protein systems, and biophysical and structural investigations with a variety of tools.
The group is also developing methods to advance imaging capabilities, ranging from microfluidic devices for handling cells and proteomes, to developing instrumentation for the preparation of cryo-electron microscopy grids from nanoliters of sample, as well as image processing approaches.