Poster Presentation 2014 International Biophysics Congress

The role of β2-microgloulin amyloid-induced membrane disruption in fibril mediated cytotoxicity (#480)

Sophia C. Goodchild 1 , Kevin W. Tipping 1 , Tania Sheynis 1 , Rebecca Thompson 1 , Wei-Feng Xue 2 , Paul A. Beales 3 , Eric W. Hewitt 1 , Sheena E. Radford 1
  1. Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds, Leeds, UK
  2. School of Biosciences, University of Kent, Canterbury, UK
  3. Astbury Centre for Structural Molecular Biology and School of Chemistry, University of Leeds, Leeds, UK

The accumulation of amyloid fibrils is associated with a number of debilitating human diseases including Alzheimer’s disease, Parkinson’s disease, type II diabetes and dialysis related amyloidosis (DRA). While the molecular mechanisms underlying these amyloid disease pathologies are not well understood, the interaction between amyloid proteins and cell membranes is thought to play an important role in amyloid induced cytotoxicity. Amyloid fibrils of β2-microgloulin (β2m), the 99-resdidue precursor of the amyloid fibrils associated with DRA, have previously been shown to cause disruption of membrane bilayers in vitro that is mirrored by a decrease in cell viability (Xue 2009). However, the effect of lipid composition and the chemical environment in which β2m-lipid interactions occur have not been investigated previously. Using a series of biophysical techniques including dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy we have investigated the effect of anionic lipid composition and pH on the susceptibility of synthetic lipid vesicles to fibril-induced membrane disruption. We show that β2m-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. These results provide new insights into the molecular mechanism of β2m amyloid-induced cell damage and suggest that the interaction between β2m fibrils and membranes of endosomal origin may facilitate the DRA disease state.

  1. Xue WF, Hellewell AL, Gosal WS et al, 2009, JBC, 284(49):34272-82