Gelsolin amyloidosis is a disease characterized by several point mutations that lead to cleavage and fibrillization of gelsolin protein. The D187 mutation to N or Y leads to aggregation of peptide fragments with the shortest aggregating peptide identified as 182SFNNGDCFILD192. Recently, G167 has also been identified as a relevant gelsolin mutation, which leads to gelsolin deposits in kidneys. Its aggregation remains to be much less understood. In vitro mechanistic evaluation of the aggregation propensities of the following gelsolin peptides: 161RLFQVKG167, and 184NNGDCFILDL193 and their respective mutants was carried out by using spectroscopic methods (fluorescence proteostat, Thioflavin T (ThT), turbidity assay, Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM)). The (non) mutant peptides containing CFILDL sequence aggregated into fibrillar networks, while certain mutants modulated aggregation. In the presence of inhibitors, Methylene Blue (MB) and Epigallocatechin gallate (EGCG), gelsolin peptide aggregation was reduced. Data indicates that inhibitors have dual functionality as aggregation inhibitors and disaggregation promoters, potentially allowing for the prevention and reversal of gelsolin amyloidosis.

Biophysical evaluations of gelsolin peptides aggregation and inhibition

ACS Spring Meeting 2021

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