Cryo-Electron Microscopy (EM) structure determination:
In this project, the master student would prepare an in-vitro protein sample for cryo-EM structure determination. The workflow involves optimizing protein expression and purification using liquid chromatography, EM grid preparation and plunge freezing, screening and imaging your samples (at the DCI Lausanne), and computational structure determination.
For more information, please contact Babatunde Ekundayo.
A central hallmark in synucleinopathies (Parkinson’s disease, multiple systems atrophy, dementia with Lewy bodies) is the misfolding of alpha-synuclein in a beta-sheet-rich state. These isoforms have a propensity to stack into elongated fibrils that can be found in the brain tissue of human patients. Various different techniques are used to understand the impact and structure of these fibrillar assemblies.
In this project, the master student would assess the impact of different conditions on the fibril structure. The workflow involves sample preparation for cryo-EM imaging (BSL-2 restricted work), screening and imaging of your samples (at the DCI Lausanne), and structure determination of the fibrils (computationally).
For more information, please contact Domenic Burger.
Correlative Light and Electron Microscopy (CLEM) on the human brain:
In these projects, the master student would prepare chemically fixed human brain tissue for high-resolution imaging with electron microscopy. For this, a continuous workflow from tissue sectioning, fluorescent staining, heavy metal staining, resin embedding, and serial sectioning with ultramicrotomy is needed. You will collect light and fluorescent microscopy images and high-resolution electron microscopy images to assess the ultrastructure of different types of inclusions.
The presence of pure characteristic disease pathology for any neurodegenerative disease is the exception rather than the rule, with the majority of brains showing multiple pathologies (co-morbidity). In this project, we aim to gain morphological and ultrastructural information from the post-mortem human brain on these pathological inclusions across a variety of neurodegenerative diseases.
For more information, please contact Amanda Lewis.
The main neuropathological hallmark of Parkinson’s Disease are Lewy bodies, however, there exists a wide spectrum of alpha-synuclein inclusions in the human brain. These different inclusions are thought to represent various stages of Lewy body formation. Apart from the presence of alpha-synuclein, very little is known about their molecular components or structural organization. In this project, we aim to use CLEM to gain ultrastructural information on these different pathologies in order to gain insight into the mechanism of Lewy body formation.
For more information, please contact Amanda Lewis.
Parkinson’s disease is the second-most common neurodegenerative disorder. Its main pathological hallmarks are Lewy bodies and alpha-synuclein inclusions in the brain and peripheral tissues (skin, gut, salivary glands) of affected patients. Interestingly, peripheral tissues are easily accessible and believed to play a crucial role in Parkinson’s disease, especially in its early stages. In this project, we aim to gain high-resolution morphological and biochemical insights into alpha-synuclein deposits in the skin from Parkinson’s disease donors.
For more information, please contact Marta Di Fabrizio.
Dementia with Lewy bodies (DLB) is another synucleinopathy where the onset of dementia precedes the onset of Parkinsonism. The neuropathological inclusions include Lewy bodies in the cortical and limbic regions alongside Alzheimer’s disease-related pathologies. In this project, we aim to gain high-resolution ultrastructural insights into alpha-synuclein deposits in the post-mortem human brain from DLB donors.
For more information, please contact Amanda Lewis.
Multiple systems atrophy belongs to the group of synucleinopathies and is a rapidly progressing neurodegenerative disease. A central hallmark of neurodegenerative diseases is the observation of tissue inclusions that are positive in alpha-synuclein. We aim to understand the morphology, temporal development, and fibril dependency of these structures. This project is directly linked to adjacent in-vitro and in-situ fibril research.
For more information, please contact Domenic Burger.
Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD) are two diseases of the same spectrum. While one Transactive response DNA binding protein 43 (TDP43) protein is the main protein component in the aggregates, observed in 97% of aggregates in ALS and 50% of aggregates in FTD. In this project, we aim to gain structural insights into the role of TDP43 pathological plaques in these diseases. To this end, we will apply correlative light and electron microscopy approach to a post-mortem patient brain.
For more information, please contact Meltem Tatli.