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: Lesley J Page, Ji Young Suk, Mary E Huff, Hee-Jong Lim, John Venable, John Yates, Jeffery W Kelly, William E Balch
• Journal: The EMBO journal (EMBO J) Vol. 24 Issue 23 Pg. 4124-32 (Dec 07 2005) ISSN: 0261-4189 [Print] England
• PMID: 16281052 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid
• Gelsolin
• Mmp14 protein, mouse
• Peptide Fragments
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases
• Matrix Metalloproteinase 14

Topics

• Amyloid (biosynthesis)
• Animals
• Cell Line
• Cell Line, Tumor
• Extracellular Matrix (physiology)
• Gelsolin (metabolism)
• Humans
• Hydrolysis
• Matrix Metalloproteinase 14
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases (physiology)
• Mice
• Peptide Fragments (biosynthesis)