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Early stages of amyloid fibrils formation elucidated by single-molecule fluorescence two-colour coincidence detection


The amyloid diseases, including for instance Alzheimer and Parkinson's diseases, are being actively investigated in recent years by biophysicists, biochemists, or neuroscientists. Despite of this, the fibrillogenesis mechanisms and the early events of fibril formation are still not well understood. Nonetheless, they are crucial for a better understanding and future improvements in healthcare particularly since there is growing evidence that it is the small oligomers that cause cell death. Therefore these early stages will be the focus of the current work. We will merge, in a multidisciplinary proposal, some standard techniques used in the amyloid field, such as light scattering or electron microscopy, and the novel single-molecule fluorescence technique of two-colour coincidence detection (TCCD).

The TCCD technique allows the sensitive detection and quantification of the self-assembly of two or more molecules, each labelled with one of two different fluorophores. Therefore, this technique provides unique and valuable information on the aggregation kinetics, different oligomer size, and relative populations of oligomers allowing the determination of the energy landscape for oligomerisation. In a first step, we will characterize the early aggregation of a model peptide system, a Transthyretin 11-aminoacids fragment (TTR 105-115). The following phases will be to elucidate oligomerization of some full-length proteins: the SH3 domain of the p85-alpha subunit of phosphatidylinositol 3-kinase (PI3-SH3), and the alpha -synuclein. The later is the pathogenic protein in Parkinson's disease.

The last goal will be to examine the influence of two classes of protein chaperone on the early aggregation of alpha-synuclein. The chaperones will be the protein HSP70 and the alpha-crystallin. The biomedical relevance of these systems and the unique information that the TCCD technique provides make the current proposal an important advance in the amyloid fibrils field.

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The Old Schools, Trinity Lane
United Kingdom