Oligomeric structure and membrane disruption by an amyloid peptide from the mammalian prion protein

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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 encephalopathies (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. In order to unravel this common mechanism for amyloid protein toxicity, we will characterize the molecular structure and membrane-binding behaviour of a neurotoxic fragment of the mammalian prion protein (PrP). In addition to forming amyloid fibrils, PrP(106-126) has been shown to form small, neurotoxic aggregates and to disrupt membranes, making it a suitable model for our studies. Using solid state nuclear magnetic resonance (NMR), we will determine the molecular structure of the toxic aggregates formed by this peptide, and define the interactions of PrP(106-126) with model cell membranes. Specifically, we will: