High-resolution cryo-EM of fibrils and proteins
We study fibrils of the protein alpha-synuclein (aSyn), which can be formed spontaneously in-vitro if a fibril seed or an air-water interface is present. Alternatively, fibrils can be prepared or seeded from post-mortem human brain tissue. We have determined the atomic structures of different conformations (prionoid strains) of aSyn fibrils (Guerrero-Ferreira et al., eLife 2018 and eLife 2020). Interestingly, polymorph-1 is not compatible with PD-relevant mutations in the gene sequence of aSyn, so that persons suffering from familial early-onset Parkinson’s disease due to such mutations in aSyn should not be able to form such polymorph 1 fibrils. However, such patients would be able to form polymorph-2 or polymorph-3 fibrils, which provide space for the mutated amino acids within the fibril architecture. It is unclear, how these fibrils contribute to the development of Parkinson’s disease.
We also study other proteins related to Parkinson’s disease and other neurodegenerative diseases, such as LRRK2.
Structural analysis of human brain
In a parallel line of research, we study the ultrastructure of human post-mortem brain tissue, retrieved during autopsy from tissue donor patients at the VUMC clinic in Amsterdam. We study human brain from patients who suffered from Parkinson’s disease (PD) or related diseases (DLB, MSA), using membrane-preserving sample preparation protocols and correlative light and electron microscopy (CLEM). We characterize the general morphology of the tissue and specifically the ultrastructure of Lewy bodies (>5 micrometer diameter blobs) that were identified by light microscopy due to their high concentration of alpha-synuclein. We found that Lewy bodies in PD are heterogeneous in shape and composition, and in the majority of cases are primarily composed of aggregated membrane fragments, while only a minority of LBs contains some filamentous material (Shahmoradian, 2019). This was a rather unexpected finding (Bartels, 2019). In contrast, when studying brain tissue from Alzheimer mouse models or Huntington’s disease patients, we find these to be primarily composed of filaments, presumably fibrillar tau tangles or TDP-43 fibrils, as expected.
In collaboration with:
- Wilma van de Berg (VUMC, Amsterdam)
- Markus Britschgi, Matthias lauer (Hoffmann-La Roche, Ltd., Basel)
- Paola Picotti (ETH Zürich)
- Roland Riek (ETH Zürich)
- Ronald Melki (CNRS, Paris)
- Jean-Marc Taymans (Lille University)
- Christel Genoud (EMF, Uni Lausanne).