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SUMMARY:Structural Analysis of Amyloid-like Protein Fibrillation - Bente V
 estergaard\,  Department of Drug Design and Pharmacology\, University of C
 openhagen
DTSTART:20160309T103000Z
DTEND:20160309T113000Z
UID:TALK64999@talks.cam.ac.uk
CONTACT:Jerome Charmet
DESCRIPTION:Protein amyloid fibrillation is associated with a number of gr
 ave diseases\, most notably the neurodegenerative diseases such as Alzheim
 er’s and Parkinson’s diseases (1). Protein and peptide fibrillation al
 so constitutes a major challenge in the biopharmaceutical industry\, where
  fibrillation must be avoided to ensure product safety (2). The structural
  investigation of protein fibrillation is however inherently challenging\,
  since a number of structural species co-exist during the fibrillation rea
 ction. These species cover a wide range of sizes (nm to µm) and exist in 
 different volume fractions over time\, in an equilibrium that is highly se
 nsitive to the experimental conditions. Isolation of individual species is
  thus not possible.\nAt the same time\, it is important to investigate the
  structural species formed during the fibrillation pathway. Not only are t
 hese key to understanding the molecular principles behind the process\, bu
 t also accumulating evidence links such intermediate species to cytotoxic 
 activity\, central to the progressive\, degenerative diseases. We use smal
 l angle X-ray scattering (SAXS) as a central method to investigate the fib
 rillation reaction. Formation of -synuclein (aSN) fibrils is associated
  with Parkinson’s disease. We have previously characterized the low-reso
 lution structure of intermediately formed aSN oligomers (3) and reveal tha
 t these oligomers are building blocks of the fibril structure (4). We have
  recently demonstrated\, that early amyloidogenic aSN species can disrupt 
 lipid model systems\, and that lipid:protein co-aggregates in a non-amyloi
 d state are formed in this context (5) while the effect on lipid membranes
  varies depending on the lipid composition (6). While the methodology behi
 nd the data analysis from such complex systems has been well elaborated bo
 th by us (7)\, and others (e.g. 8)\, the need for a robust\, objective and
  (semi-)automated analysis system is evident\, and our latest efforts in t
 his direction will be presented. We apply the newly developed software to 
 the analysis of a familial mutant of  aSN\, revealing the occurrence of in
 termediate species which have a different nature than those previously cha
 racterized (unpublished results).\n\n\nReferences: \n1. Eisenberg & Jucker
  (2012) Cell\, 148\, 1188-1203\n2. Das (2012) AAPS PharmSciTech 13\, 732-7
 46\n3. Giehm et al. (2011) PNAS\, 108\, 3246-3251\n4. Pedersen et al. (201
 5) Scientific Reports\, 5\, 10422\n5. van Maarschalkerweerd et al (2014) B
 iomacromolecules 15\, 3643-3654\n6. van Maarschalkerweerd et al. in review
 \n7. Langkilde & Vestergaard (2012) Methods. Mol. Biol. 849\, 137-155\n8. 
 Lorenzen et al. (2014) JACS 136\, 3859-3868
LOCATION:Department of Chemistry\, Cambridge\, Unilever lecture theatre
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