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 Ca2+‐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 C-terminal 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 heavy‐chain 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 99mTc‐based imaging agent in the gelsolin amyloidosis mouse model.
Part of the book: Exploring New Findings on Amyloidosis