Abstract
Protein aggregate formation is linked with multiple amyloidoses, including Alzheimer‘s and Parkinson‘s diseases. Currently, the understanding of such fibrillar structure formation and propagation is still not sufficient, the outcome of which is a lack of potent, anti-amyloid drugs. The environmental conditions used during in vitro protein aggregation assays play an important role in determining both the aggregation kinetic parameters, as well as resulting fibril structure. In the case of alpha-synuclein, ionic strength has been shown as a crucial factor in its amyloid aggregation. In this work, we examine a large sample size of alpha-synuclein aggregation reactions under thirty different ionic strength and protein concentration combinations and determine the resulting fibril structural variations using their dye-binding properties, secondary structure and morphology. We show that both ionic strength and protein concentration determine the structural variability of alpha-synuclein amyloid fibrils and that sometimes even identical conditions can result in up to four distinct types of aggregates.
Highlights
Protein amyloid aggregation into insoluble fibrillar aggregates is linked with the onset and progression of multiple amyloidoses [1], including the widespread neurodegenerative Alzheimer‘s and Parkinson‘s diseases [2,3]
We show a shift in fibril structure variability based on the initial ionic strength and protein concentration, as well as outlier samples, which contain distinct structural and morphological features
Alpha-synuclein aggregation was tracked under six different ionic strength conditions
Summary
Protein amyloid aggregation into insoluble fibrillar aggregates is linked with the onset and progression of multiple amyloidoses [1], including the widespread neurodegenerative Alzheimer‘s and Parkinson‘s diseases [2,3]. Despite years of research and growing number of such disorders [4], the overall process of protein aggregate formation is still not fully understood [5]. The complex nature of fibrillization and the resulting types of aggregates has led to the development of very few anti-amyloid drugs [6,7], with most potential compounds failing at various stages of clinical trials [8,9]. Since the number of patients affected by such protein aggregates is estimated to continue to rise over the few decades [10,11], it is critically important to obtain a better understanding of protein fibrillization in the hopes of finding a potent cure or treatment
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