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ATTENTION !!! Changement de salle !!! Structural analysis of amyloid-like protein fibrillation using small angle X-ray scattering as a central tool

Mardi 24 mars 2015 11:00 - Duree : 1 heure
Lieu : ILL 4, Seminar Room, 71 avenue des Martyrs - Grenoble

Orateur : Bente VESTERGAARD (University of Copenhagen, Department of Drug Design and Pharmacology)

Protein amyloid fibrillation is associated with a number of grave diseases, most notably the neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases (Eisenberg & Jucker (2012) Cell, 148, 1188-1203). Protein and peptide fibrillation also constitutes a major challenge in the pharmaceutical industry, where fibrillation must be avoided to ensure product safety (Das (2012) AAPS PharmSciTech 13, 732-746). The structural investigation of protein fibrillation is however inherently challenging, since a number of structural species co-exist during the fibrillation reaction. These species cover a wide range of sizes (nm to µm) and exist in different volume fractions over time, in an equilibrium highly sensitive to the experimental conditions. Isolation of individual species is thus not possible.

At the same time, it is important to investigate the structural species formed during the fibrillation pathway. Not only are these key to understanding the molecular principles behind the process, but also accumulating evidence links such intermediate species to cytotoxic activity, central to the progressive, degenerative diseases. We use small angle X-ray scattering (SAXS) as a central method to investigate the fibrillation reaction. Formation of alpha-synuclein fibrils is associated with Parkinson’s disease. We have characterized the low-resolution structure of intermediately formed alpha-synuclein oligomers (Giehm et al. (2011) PNAS, 108, 3246-3251) and reveal that these oligomers are building blocks of the fibril structure (Pedersen et al. (2015) Scientific Reports, accepted with revision). We have recently demonstrated, that early amyloidogenic aSN species can disrupt lipid model systems, and that lipid:protein co-aggregates in a non-amyloid state are formed in this context (van Maarschalkerweerd et al (2014) Biomacromolecules 15, 3643-3654) while the effect on lipid membranes varies depending on the lipid composition (van Maarschalkerweerd et al. in review). We have also shown that transthyretin fibrils under particular experiemental conditions co-exist with a highly unfolded monomeric species, potentially providing important links to both cytotoxicity and the nucleation principles behind fibrillation (Groenning et al. Scientific Reports, accepted with revision).

Contact : deme@ill.fr

Discipline évènement : (Physique)
Entité organisatrice : (ILL)
Nature évènement : (Séminaire)
Evènement répétitif : (General ILL Seminar - College 8)
Site de l'évènement : Polygone scientifique

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