Facebook Pixel Code
Banner image
Sharpe Lab

Membrane disruption by aggregative proteins

Role of protein-membrane interactions in diseases of protein misfolding

The accumulation of misfolded or aggregated protein in a fibrillar form is characteristic of several human diseases including amyloid diseases, such as type II diabetes and Alzheimer's disease, as well as spongiform encephalopaties (prion diseases). These diseases are related to the misfolding of different proteins, and exhibit different mechanisms for infectivity, however growing evidence points to a common mechanism for the cytotoxicity of the misfolded proteins. Specifically, it has been proposed that cell death is caused by small protein aggregates.

Recent studies have indicated that these toxic aggregates are able to directly kill cells by disrupting their membranes; possibly through formation of channels or holes in the plasma membrane, or simply by inducing leakage of cell contents, and that this leads to cell death and progression of the disease state (How might this happen?).

In order to unravel this common mechanism for amyloid protein toxicity, we are characterizing the molecular structure and membrane-binding behaviour of model neurotoxic peptides derived from the mammalian prion protein. Knowledge of the structures adopted by aggregative proteins at model membranes, and their effect on bilayer integrity, will provide insight into the basis for cell death caused by amyloid and prion proteins.