Source:http://linkedlifedata.com/resource/pubmed/id/19904968
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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
48
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pubmed:dateCreated |
2009-12-1
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pubmed:abstractText |
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.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
1520-4995
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pubmed:author | |
pubmed:issnType |
Electronic
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pubmed:day |
8
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pubmed:volume |
48
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
11370-80
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pubmed:dateRevised |
2011-3-3
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pubmed:meshHeading |
pubmed-meshheading:19904968-Amyloid,
pubmed-meshheading:19904968-Amyloidosis,
pubmed-meshheading:19904968-Electrophoresis, Polyacrylamide Gel,
pubmed-meshheading:19904968-Gelsolin,
pubmed-meshheading:19904968-Humans,
pubmed-meshheading:19904968-Microscopy, Atomic Force,
pubmed-meshheading:19904968-Molecular Weight,
pubmed-meshheading:19904968-Peptide Fragments,
pubmed-meshheading:19904968-Spectrometry, Fluorescence
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pubmed:year |
2009
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pubmed:articleTitle |
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.
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pubmed:affiliation |
Department of Chemistry, Skaggs Institute for Chemical Biology, La Jolla, California 92037, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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