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Transthyretin Amyloidosis: Chaperone Concentration Changes and Increased Proteolysis in the Pathway to Disease.

da Costa G, Ribeiro-Silva C, Ribeiro R, Gilberto S, Gomes RA, Ferreira A, Mateus É, Barroso E, Coelho AV, Freire AP, Cordeiro C - PLoS ONE (2015)

Bottom Line: Transthyretin amyloidosis is a conformational pathology characterized by the extracellular formation of amyloid deposits and the progressive impairment of the peripheral nervous system.Point mutations in this tetrameric plasma protein decrease its stability and are linked to disease onset and progression.We discovered, using a differential proteomics approach, that extracellular chaperones such as fibrinogen, clusterin, haptoglobin, alpha-1-anti-trypsin and 2-macroglobulin are overrepresented in transthyretin amyloidosis.

View Article: PubMed Central - PubMed

Affiliation: Centro de Química e Bioquímica, FCUL, Campo Grande, Lisboa, Portugal.

ABSTRACT
Transthyretin amyloidosis is a conformational pathology characterized by the extracellular formation of amyloid deposits and the progressive impairment of the peripheral nervous system. Point mutations in this tetrameric plasma protein decrease its stability and are linked to disease onset and progression. Since non-mutated transthyretin also forms amyloid in systemic senile amyloidosis and some mutation bearers are asymptomatic throughout their lives, non-genetic factors must also be involved in transthyretin amyloidosis. We discovered, using a differential proteomics approach, that extracellular chaperones such as fibrinogen, clusterin, haptoglobin, alpha-1-anti-trypsin and 2-macroglobulin are overrepresented in transthyretin amyloidosis. Our data shows that a complex network of extracellular chaperones are over represented in human plasma and we speculate that they act synergistically to cope with amyloid prone proteins. Proteostasis may thus be as important as point mutations in transthyretin amyloidosis.

No MeSH data available.


Related in: MedlinePlus

Plasma from ATTR individuals presents a higher proteolytic activity.A- Proteolytic activity of control and ATTR plasma measured by fluorescent protease assay kit. B–Sequence coverage obtained for three spots identified as albumin with decreased molecular weight.
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pone.0125392.g003: Plasma from ATTR individuals presents a higher proteolytic activity.A- Proteolytic activity of control and ATTR plasma measured by fluorescent protease assay kit. B–Sequence coverage obtained for three spots identified as albumin with decreased molecular weight.

Mentions: A striking observation in 2DE of plasma from ATTR relatively to controls is the presence of a large set of proteins with a lower apparent molecular weight than it’s predicted value, which could indicate the presence of proteolytic fragments. For the majority of these cases we observed a decrease in sequence coverage for proteins identified by mass spectrometry and these proteins were identified at a lower molecular weight than the theoretical one (Fig 3B). We can observe the same protein in several spots with decreasing molecular mass. Take for example serum albumin which was detected in the spots 2205, 3177 and 4796 with approximate molecular weight of 70 kDa, 40 kDa and 15 kDa, respectively. Also fibrinogen alpha chain was detected in several spots of decreasing mass (spots 2391, 2653 and 4461 with respective molecular masses of 70, 50 and 15 kDa). These observations made us question about a higher proteolytic activity in the plasma of ATTR individuals. We tested this hypothesis by measuring the proteolysis of casein in our plasma samples and, as shown in Fig 2C, we observed a significant increase in the proteolytic activity in the plasma of ATTR patients with a p-value for the t-test of 9.2583E-12.


Transthyretin Amyloidosis: Chaperone Concentration Changes and Increased Proteolysis in the Pathway to Disease.

da Costa G, Ribeiro-Silva C, Ribeiro R, Gilberto S, Gomes RA, Ferreira A, Mateus É, Barroso E, Coelho AV, Freire AP, Cordeiro C - PLoS ONE (2015)

Plasma from ATTR individuals presents a higher proteolytic activity.A- Proteolytic activity of control and ATTR plasma measured by fluorescent protease assay kit. B–Sequence coverage obtained for three spots identified as albumin with decreased molecular weight.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4492746&req=5

pone.0125392.g003: Plasma from ATTR individuals presents a higher proteolytic activity.A- Proteolytic activity of control and ATTR plasma measured by fluorescent protease assay kit. B–Sequence coverage obtained for three spots identified as albumin with decreased molecular weight.
Mentions: A striking observation in 2DE of plasma from ATTR relatively to controls is the presence of a large set of proteins with a lower apparent molecular weight than it’s predicted value, which could indicate the presence of proteolytic fragments. For the majority of these cases we observed a decrease in sequence coverage for proteins identified by mass spectrometry and these proteins were identified at a lower molecular weight than the theoretical one (Fig 3B). We can observe the same protein in several spots with decreasing molecular mass. Take for example serum albumin which was detected in the spots 2205, 3177 and 4796 with approximate molecular weight of 70 kDa, 40 kDa and 15 kDa, respectively. Also fibrinogen alpha chain was detected in several spots of decreasing mass (spots 2391, 2653 and 4461 with respective molecular masses of 70, 50 and 15 kDa). These observations made us question about a higher proteolytic activity in the plasma of ATTR individuals. We tested this hypothesis by measuring the proteolysis of casein in our plasma samples and, as shown in Fig 2C, we observed a significant increase in the proteolytic activity in the plasma of ATTR patients with a p-value for the t-test of 9.2583E-12.

Bottom Line: Transthyretin amyloidosis is a conformational pathology characterized by the extracellular formation of amyloid deposits and the progressive impairment of the peripheral nervous system.Point mutations in this tetrameric plasma protein decrease its stability and are linked to disease onset and progression.We discovered, using a differential proteomics approach, that extracellular chaperones such as fibrinogen, clusterin, haptoglobin, alpha-1-anti-trypsin and 2-macroglobulin are overrepresented in transthyretin amyloidosis.

View Article: PubMed Central - PubMed

Affiliation: Centro de Química e Bioquímica, FCUL, Campo Grande, Lisboa, Portugal.

ABSTRACT
Transthyretin amyloidosis is a conformational pathology characterized by the extracellular formation of amyloid deposits and the progressive impairment of the peripheral nervous system. Point mutations in this tetrameric plasma protein decrease its stability and are linked to disease onset and progression. Since non-mutated transthyretin also forms amyloid in systemic senile amyloidosis and some mutation bearers are asymptomatic throughout their lives, non-genetic factors must also be involved in transthyretin amyloidosis. We discovered, using a differential proteomics approach, that extracellular chaperones such as fibrinogen, clusterin, haptoglobin, alpha-1-anti-trypsin and 2-macroglobulin are overrepresented in transthyretin amyloidosis. Our data shows that a complex network of extracellular chaperones are over represented in human plasma and we speculate that they act synergistically to cope with amyloid prone proteins. Proteostasis may thus be as important as point mutations in transthyretin amyloidosis.

No MeSH data available.


Related in: MedlinePlus