title: The 8 and 5 kDa fragments of plasma gelsolin form amyloid fibrils by a nucleated polymerization mechanism, while the 68 kDa fragment is not amyloidogenic.
abstract: Familial amyloidosis of Finnish type (FAF), or gelsolin amyloidosis, is a systemic amyloid disease caused by a mutation (D187N/Y) in domain 2 of human plasma gelsolin, resulting in domain 2 misfolding within the secretory pathway. When D187N/Y gelsolin passes through the Golgi, furin endoproteolysis within domain 2 occurs as a consequence of the abnormal conformations that enable furin to bind and cleave, resulting in the secretion of a 68 kDa C-terminal fragment (amino acids 173-755, C68). The C68 fragment is cleaved upon secretion from the cell by membrane type 1 matrix metalloprotease (MT1-MMP), affording the 8 and 5 kDa fragments (amino acids 173-242 and 173-225, respectively) comprising the amyloid fibrils in FAF patients. Herein, we show that the 8 and 5 kDa gelsolin fragments form amyloid fibrils by a nucleated polymerization mechanism. In addition to demonstrating the expected concentration dependence of a nucleated polymerization reaction, the addition of preformed amyloid fibrils, or "seeds", was shown to bypass the requirement for the formation of a high-energy nucleus, accelerating 8 and 5 kDa D187N gelsolin amyloidogenesis. The C68 fragment can form small oligomers, but not amyloid fibrils, even when seeded with preformed 8 kDa fragment plasma gelsolin fibrils. Because the 68 kDa fragment of gelsolin does not form amyloid fibrils in vitro or in a recently published transgenic mouse model of FAF, we propose that administration of an MT1-MMP inhibitor could be an effective strategy for the treatment of FAF.
authors.affiliation: Department of Chemistry, Skaggs Institute for Chemical Biology, La Jolla, California 92037, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Solomon
authors.forename: Isaac T
authors.initials: IT
authors.lastname: Yonemoto
authors.forename: Amber N
authors.initials: AN
authors.lastname: Murray
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Price
authors.forename: Evan T
authors.initials: ET
authors.lastname: Powers
authors.forename: William E
authors.initials: WE
authors.lastname: Balch
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D000682:Amyloid / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D018260:Gelsolin / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D018625:Microscopy, Atomic Force; D008970:Molecular Weight; D010446:Peptide Fragments / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D013050:Spectrometry, Fluorescence
chemical_list: D000682:Amyloid; D018260:Gelsolin; D010446:Peptide Fragments