A Nanobody‐Based Approach to Amyloid Diseases, the Gelsolin Case Study

Abstract

Gelsolin amyloidosis (AGel) is an autosomal-dominant inherited disease caused by point mutations in the gelsolin gene. At the protein level, these mutations result in the loss of a Ca 2+ -binding site, crucial for the correct folding and function. In the trans-Golgi network, this mutant plasma gelsolin is cleaved by furin, giving rise to a 68 kDa Cterminal fragment. When secreted in the extracellular matrix, this fragment undergoes proteolysis by MT1-MMP-like proteases, resulting in the production of 8 and 5 kDa amyloidogenic peptides. Nanobodies, the variable part of the heavy chain of heavychain antibodies, have been used as molecular chaperones for mutant plasma gelsolin and the 68 kDa C-terminal fragment in an attempt to inhibit their pathogenic proteolysis. Furthermore, these nanobodies have also been tested and applied as a 99m Tc-based imaging agent in the gelsolin amyloidosis mouse model.