Gelsolin is an actin-binding protein responsible for the remodelling of the actin cytoskeleton. Under pathological conditions, Gelosolin is susceptible to aberrant proteolytic cleavage. The D187N and D187Y point mutations have been associated with fragmentation, causing the formation of amyloidogenic 8kDa (173–242) and 5 kDa (173–225) fragments. The fragments systematically deposit within the organs to promote cell death&lt;span style="font-size:10.8333px"&gt;.&lt;/span&gt; Wildtype peptides within the same sequence do not demonstrate similar aggregation propensity or amyloid formation. Gelsolin protein is also capable of propagating a diseased state across cells through the process of seeding. Despite the detrimental effects of Gelsolin mutation, the mechanism of amyloid formation is understudied. Herein, we investigated the aggregation propensities, inhibition, and morphology of wild-type Gelsolin peptides (187-193) and their associated mutants under physiological conditions. We also explored the seeding reaction of Gelsolin with high-concentration mutant peptides to monitor the propagation of the diseased state. Spectroscopic and microscopic methods allowed for the identification and visualization of aggregates and amyloids. We reported that CFILDL-containing peptides were prone to aggregation, which may be inhibited and reversed with small molecules. The seeding of Gelsolin peptides promoted aggregation and fibril formation. Of note is the unique behaviour of peptide mutants with respect to their aggregation propensities pointing to their biological relevance. Treating aberrant Gelsolin aggregates may be a foundation for improving outcomes of similar amyloidogenic diseases.

Gelsolin aggregation and inhibition: Biophysical characterization

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