Role of proprotein convertases in the pathogenic processing of the amyloidosis-associated form of secretory gelsolin

Abstract

Familial amyloidosis of the Finnish type (FAF) is caused by two proteolytic cleavages of mutant gelsolin leading to the accumulation of FAF amyloid in the patients' tissues. Here, we demonstrate that, in mouse pituitary corticotropic AtT20 cells, the enzyme responsible for the first cleavage of mutant secretory FAF gelsolin to FAF amyloid precursor is present in reasonable amounts. Furthermore, in At T20 cells stably expressing α1-PDX, a potent inhibitor of most proprotein convertases, this cleavage was inhibited. The present data provide strong evidence that proprotein convertases, possibly furin or PC5, are involved in the initial pathological cleavage of mutant secretory FAF gelsolin leading ultimately to the amyloid disease.