title: Metalloendoprotease cleavage triggers gelsolin amyloidogenesis.
abstract: Amyloid diseases like Alzheimer's disease and familial amyloidosis of Finnish type (FAF) stem from endoproteolytic cleavage of a precursor protein to generate amyloidogenic peptides that accumulate as amyloid deposits in a tissue-specific manner. FAF patients deposit both 8 and 5 kDa peptides derived from mutant (D187Y/N) plasma gelsolin in the extracellular matrix (ECM). The first of two aberrant sequential proteolytic events is executed by furin to yield a 68 kDa (C68) secreted fragment. We now identify the metalloprotease MT1-matrix metalloprotease (MMP), an integral membrane protein active in the ECM, as a protease that processes C68 to the amyloidogenic peptides. We further demonstrate that ECM components are capable of accelerating gelsolin amyloidogenesis. Proteolysis by MT1-MMP-like proteases proximal to the unique chemical environment of the ECM offers an explanation for the tissue-specific deposition observed in FAF and provides critical insight into new therapeutic strategies.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Page
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Suk
authors.forename: Mary E
authors.initials: ME
authors.lastname: Huff
authors.forename: Hee-Jong
authors.initials: HJ
authors.lastname: Lim
authors.forename: John
authors.initials: J
authors.lastname: Venable
authors.forename: John
authors.initials: J
authors.lastname: Yates
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.forename: William E
authors.initials: WE
authors.lastname: Balch
mesh_terms: D000682:Amyloid / Q000096:biosynthesis*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000502:physiology; D018260:Gelsolin / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D053511:Matrix Metalloproteinase 14; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000502:physiology*; D051379:Mice; D010446:Peptide Fragments / Q000096:biosynthesis
chemical_list: D000682:Amyloid; D018260:Gelsolin; C507096:Mmp14 protein, mouse; D010446:Peptide Fragments; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14