Furin initiates gelsolin familial amyloidosis in the Golgi through a defect in Ca2+ stabilization

Hereditary familial amyloidosis of Finnish type (FAF) leading to amyloid in the peripheral and central nervous systems stems from deposition of a 71 r esidue fragment generated from the D187N/Y variants of plasma gelsolin by t wo sequential endoproteolytic events. We identify the protease accomplishin g the first cleavage as furin, a proprotein convertase. Endoproteolysis of plasma gelsolin occurs in the trans-Golgi network due to the inability of t he FAF variants to bind and be stabilized by Ca2+. Secretion and processing of the FAF variants by furin can be uncoupled by blocking the convergence of the exocytic pathway transporting plasma gelsolin and the endocytic recy cling of furin. We propose that coincidence of membrane trafficking pathway s contributes to the development of proteolysis-initiated amyloid disease.