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SUMMARY:Amyloid oligomers : precursors\, competitors or inhibitors of fibr
 il formation - Professor Martin Muschol\, Dept. of Physics\, University of
  South Florida
DTSTART:20170419T093000Z
DTEND:20170419T103000Z
UID:TALK71979@talks.cam.ac.uk
CONTACT:23027
DESCRIPTION:Accumulation of insoluble protein fibrils with a characteristi
 c cross-beta sheet structure is intimately associated with a multitude 
 of human disorders ranging from Alzheimer's and Parkinson's disease to typ
 e-II diabetes.  Understanding the molecular mechanisms regulating and prom
 oting the formation of distinct species of amyloid aggregates in vitro and
  in vivo represents a critical step towards devising effective treatment s
 trategies. \n \nWe have mapped out conditions for in vitro assembly of hen
  egg-white lysozyme into distinct amyloid species.  Varying protein and sa
 lt concentrations\, we observed three distinct growth regimes separated by
  sharp transition boundaries.  At low salt/protein concentrations\, “tra
 ditional” rigid fibrils formed.  Upon crossing a salt- and protein-speci
 fic threshold\, globular oligomers and their closely related curvilinear p
 olymers emerged\, which transitioned into ‘amorphous’ precipitation up
 on further increases in either solution parameter.  These distinct assembl
 y products displayed unique aggregation kinetics\, morphologies and struct
 ural characteristics\, as determined from in situ dynamic light scattering
 \, fluorescence spectroscopy\, atomic force microscopy and infrared spectr
 oscopy.  A colloidal model that accounts for protein charge repulsion and 
 salt-mediated charge screening replicated both the sharp onset of oligomer
  formation and its dependence on solution conditions.  \n\nUsing this phas
 e diagram\, we investigated the transition from oligomer-free to oligomeri
 c fibril growth.  Specifically we explored whether amyloid oligomers were 
 precursors to\, or off-pathway competitors of lysozyme fibril growth.  We 
 will present evidence that lysozyme oligomers\, instead of promoting or co
 mpeting with fibril formation\, actively inhibit fibril nucleation in vitr
 o.  Such insight could prove important due to the critical role amyloid ol
 igomers are believed to play in the etiology of amyloid diseases.\n
LOCATION:Unilever Lecture Theatre\,  Department of Chemistry
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