Abstract

What are the molecular mechanisms that govern the amyloid fibrils’ potential to seed the formation of new amyloid to facilitate their spreading, and to damage cells in amyloid-associated diseases such as Alzheimer’s disease, Parkinson’s disease, type 2 diabetes, and systemic amyloidoses? These disease-associated properties of amyloid have been linked to small nano-sized particles created through the fragmentation of amyloid fibrils, which is a process governed by the stability of amyloid fibrils toward breakage. We have previously described an approach that is capable of resolving fibril fragmentation rates, fibril particle concentrations, and fibril length distributions, through direct observations by atomic force microscopy image analysis. Applying our approach to several different amyloid model systems, such as alpha-synuclein, lysozyme, and the yeast prion protein Sup35NM, we present an unique comparison of the stability of these different amyloid fibrils toward breakage. Using the yeast prion protein Sup35NM that forms amyloid particles capable of conferring district yeast phenotypes in vivo, we have also quantified the biological impact of fibril fragments in terms of their transmissive potential. Our results allow new quantitative insights into key properties of amyloid aggregated in terms of their their destructive association to disease as well as the constructive potential they have for future functional amyloid materials development.