Neurodegenerative or protein-misfolding diseases such as prion-related encephalopathies are distinguished by the aggregation of misfolded proteins which leads to the cumulative loss of neurons in the areas of aggregation. The majority of the protein aggregates found in neurodegenerative diseases form extended, β-sheet-rich, proteinaceous fibrillar structures commonly classified as amyloids. A prion is defined as an infectious protein that can trigger fatal neurodegenerative diseases.  The transmissible nature of prions stems from its ability to misfold and further propagate by transmitting its misfolded state. To understand the aggregation kinetics and morphology of prions, we selected non-infectious fragments of the cellular prion protein associated with bovine spongiform encephalopathy to study via atomic force microscopy.   Atomic force microscopy allows for the characterization of nanoscale objects and the observation of changes associated with protein aggregation while at physiological conditions.  We hypothesize each prion peptide in this study will have unique amyloid-forming kinetics and morphologies which will be affected by the introduction of various interfaces (air/liquid, liquid/solid, or lipid membrane) to present similar chemistry to the brain.  Using atomic force microscopy, we observe how the formation of stable, morphologically distinct amyloidogenic prion aggregates on various surfaces is dependent upon concentration, temperature, amino acid sequence, surface chemistry, and location within the prion protein fragment. Additionally, we utilize the following biophysical techniques to characterize aggregation: Thioflavin T kinetic aggregation assays to quantify the extent of amyloid aggregation over time, lipid/polydiacetylene vesicle biosensing assays to measure peptide-lipid interactions, and ultracentrifugation assays to separate oligomers from fibrils.  These studies will provide insight into how surfaces promote polymorphic aggregation and have significant impact in the development of the infectious nature of prion aggregation.

Characterizing prion peptide aggregation and surface interactions by means of atomic force microscopy

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