Towards a quantitative understanding of in vivo protein aggregation. (360G-Wellcome-082683_Z_07_Z)

Assemblies of misfolded proteins are associated with a range of neurological and systemic human disorders whose detailed molecular mechanisms are not understood in any detail. Key for generating a better understanding of protein interactions and dynamics is the synergy between experiment and theory, which creates a link between protein chemistry and human diseases. This proposal describes the use of computational methods in combination with biophysical experiments and studies of Drosophila model s and aims to reveal the molecular processes involved in protein assembly. By using alpha-synuclein as a model system, a protein of great medical relevance that is highly tractable both experimentally and computationally, I aim to develop a quantitative understanding of in vivo aggregation. To achieve this, I will generate rationally an extensive set of alpha-synuclein variants and analyse their in vitro aggregation mechanism in the presence of different biological factors. These results, combin ed with the measured effect of these variants on neurodegeneration in transgenic Drosophila, will be used to develop a mathematical description of in vivo protein aggregation. As well as providing unprecedented knowledge of the mechanism of protein association, the goal is also to develop widely applicable methods of screening amyloidogenicity of entire proteomes and of preventing assembly.