Growth, assembly and fragmentation mechanisms in the molecular life cycle of Sup35NM prion and alpha-synuclein amyloid particles

With devastating diseases like Alzheimer's disease and Parkinson's disease rising in numbers, amyloid and prion research is steadily increasing. However, there are many questions that have yet to be answered. One such question is how their life cycle relates to their transmissibility and hence nature of being an amyloid or prion, as well as how it relates to their disease association or beneficial functionality. Through the use of ThT fluorescence curves and atomic force microscopy (AFM) imaging, this study compared the elongation and fragmentation rates in the life cycle of Sup35NM, a functional prion, to α-synuclein, a prion-like amyloid associated with Parkinson's disease. Using sonication at a reduced amplitude as a method of mechanical perturbation, it was determined that fibrils formed by Sup35NM have a significantly lower stability to these conditions than those formed by α-synuclein. Seeds produced during the fragmentation assays were then used to explore the initial rates of elongation. This allowed a striking difference in elongation rates to be imaged through the use of AFM, where Sup35NM fibrils elongated at an increased rate relative to α-synuclein. The increased stability and reduced elongation rate of α-synuclein fibrils would suggest a slow growth of aggregated material and a reduced ability to fragment which would lower the ability to be transferred between cells of an individual. This would be biologically beneficial as would lower the spread and impact of any associated disease and hence could be the product of a biological drive to favour αsynuclein to form fibrils that have these properties. Sup35NM behaves in the reverse, with a low stability and high elongation rate. These would allow a large number of small seeds to be produced rapidly, which would facilitate the spread of aggregates between individual yeast cells and speed up their growth once they enter the cell. As a functional prion, these properties are desirable as would allow the rapid activation of their associated phenotype within an individual as well as its neighbours. This again could suggest that as these properties would be favoured they would be selected for