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The Time-and Spatially Resolved Aggregation of a-Synuclein and its Relationship to Cell-Cell Transmissibilty
Third-party funded project |
Project title |
The Time-and Spatially Resolved Aggregation of a-Synuclein and its Relationship to Cell-Cell Transmissibilty |
Principal Investigator(s) |
Stahlberg, Henning
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Co-Investigator(s) |
Scheiwiller, Marcel
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Organisation / Research unit |
Departement Biozentrum / Structural Biology (Stahlberg) |
Project start |
01.09.2014 |
Probable end |
31.08.2017 |
Status |
Completed |
Abstract |
The self-association of identical proteins into macroscopic entities with toxic and/or functional activities is an omnipresent process. Some protein aggregates exhibit a cross-β-sheet structure and are associated with several human diseases including Alzheimer’s and Parkinson’s disease (PD), but may also have a non-pathological function. This interdisciplinary proposal aims to obtain a detailed mechanistic understanding of the structural and cellular basis of the cell-to-cell transmissibility of α-synuclein (α-syn) aggregates, which are associated with PD. In particular it focuses on in vitro and in-cell studies of the spatially and time-resolved formation of seeds, the replication of amyloids, the role of the subcellular milieu in these processes, and the elucidation of environment-dependent amyloid polymorphisms and their relationship to transmissibility and toxicity. We propose to study the kinetics and structures of protein aggregation in vitro under a plethora of physiologically relevant conditions covering intracellular compartments (RR) and beyond, and to correlate these finding with the in-cell aggregation monitored by electron microscopy (EM) (HS) and super resolution fluorescence microscopy (SR) (JR), accompanied by cell biology studies on the transmissibility and the intracellular route of the infectious material (LR). Using this rather unique combination of techniques applied to both in vitro and in-cell studies, will give insight into (i) the relationships between the aggregation kinetics of α-syn, its localization to specific intracellular compartments and its cell-to-cell transmissibility and (ii) the relationship between cell toxicity and transmissibility. |
Financed by |
Other sources
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24/04/2024
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