WP 1 Understanding misfolding, amyloid and toxicity
Although the impact of amyloidoses on public human health and economy is broadly recognized little is known about the details of the determinants of these diseases at the atomic level. This knowledge is however crucial to understand the principle of misfolding and aggregation and to design therapeutic strategies to combat this family of disorders.
Our objectives are therefore to understand at the atomic level i) the mechanisms leading to protein misfolding and aggregation by determining the structural characteristics of the various species populated during amyloid fibril formation and ii) the toxicity of the various species and the molecular mechanism by which it is generated. As an additional objective, we investigate the ability of a series of small molecules to interfere with the process of aggregation and cytotoxicity.
The complexity of these tasks requires the concomitant utilisation of theoretical approaches and of sophisticated and diverse experimental techniques ranging from spectroscopy to protein engineering. We are studying a series of amyloidogenic proteins including both those representative of the generic nature of the ability to form amyloid structures [acetylphosphatase (AcP) and immunoglobulin domains (Ig)] and those associated with pathological conditions [beta-2-microglobulin (b2-m), islet amyloid peptide, (IAPP) apolipoprotein A1 (apoA1), human lysozyme (HuL), and transthyretin (TTR)].
A large amount of data has been obtained during the EURAMY work and will soon appear on this place.
