Limits...
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

Extracellular Chaperones are overrepresented in DLT individuals—SDS-PAGE analysis of plasma proteins from four individuals after orthotic liver transplantation (OLT) and four individuals after domino transplantation (DLT) and Western blot to detect TTR, Fibrinogen, Alpha 1 anti-trypsin (ITI), Vitamin D binding protein (VBP), alpha 2 microglobolin and C-reactive protein (CRP).Molecular weight markers are represented on the left hand of the figure and included in the western blots as blue markers.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492746&req=5

pone.0125392.g002: Extracellular Chaperones are overrepresented in DLT individuals—SDS-PAGE analysis of plasma proteins from four individuals after orthotic liver transplantation (OLT) and four individuals after domino transplantation (DLT) and Western blot to detect TTR, Fibrinogen, Alpha 1 anti-trypsin (ITI), Vitamin D binding protein (VBP), alpha 2 microglobolin and C-reactive protein (CRP).Molecular weight markers are represented on the left hand of the figure and included in the western blots as blue markers.

Mentions: We previously observed that fibrinogen expression is increased in ATTR patients [39] and this result was confirmed in this work, in which several spots of fibrinogen were over expressed in ATTR patients. Since most TTR is produced by the liver, the progression of the disease can be halted by OLT, which leads to the disappearance of the V30M TTR form of the transplant recipient [40]. To obviate the shortage of livers available for transplantation, DLT was introduced in which a liver from a ATTR patient is transplanted to a patient with liver failure. DLT introduces mutated TTR variants in circulation, increasing the risk of ATTR development. To evaluate if DLT individuals presented the same increased levels of the proteins observed in ATTR individuals we collected samples of individuals that were subjected to OLT and DLT and monitored expression of fibrinogen, Vitamin D binding protein, Alpha 2 macroglobolin and alpha 1 anti-trypsin by western blot analysis. As shown in Fig 2, these proteins are also found to be overrepresented in DLT individuals, but not in OLT individuals. TTR and the C-reactive protein, a prototypic acute phase protein, levels do not present any significative difference between DLT and OLT individuals.


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)

Extracellular Chaperones are overrepresented in DLT individuals—SDS-PAGE analysis of plasma proteins from four individuals after orthotic liver transplantation (OLT) and four individuals after domino transplantation (DLT) and Western blot to detect TTR, Fibrinogen, Alpha 1 anti-trypsin (ITI), Vitamin D binding protein (VBP), alpha 2 microglobolin and C-reactive protein (CRP).Molecular weight markers are represented on the left hand of the figure and included in the western blots as blue markers.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0125392.g002: Extracellular Chaperones are overrepresented in DLT individuals—SDS-PAGE analysis of plasma proteins from four individuals after orthotic liver transplantation (OLT) and four individuals after domino transplantation (DLT) and Western blot to detect TTR, Fibrinogen, Alpha 1 anti-trypsin (ITI), Vitamin D binding protein (VBP), alpha 2 microglobolin and C-reactive protein (CRP).Molecular weight markers are represented on the left hand of the figure and included in the western blots as blue markers.
Mentions: We previously observed that fibrinogen expression is increased in ATTR patients [39] and this result was confirmed in this work, in which several spots of fibrinogen were over expressed in ATTR patients. Since most TTR is produced by the liver, the progression of the disease can be halted by OLT, which leads to the disappearance of the V30M TTR form of the transplant recipient [40]. To obviate the shortage of livers available for transplantation, DLT was introduced in which a liver from a ATTR patient is transplanted to a patient with liver failure. DLT introduces mutated TTR variants in circulation, increasing the risk of ATTR development. To evaluate if DLT individuals presented the same increased levels of the proteins observed in ATTR individuals we collected samples of individuals that were subjected to OLT and DLT and monitored expression of fibrinogen, Vitamin D binding protein, Alpha 2 macroglobolin and alpha 1 anti-trypsin by western blot analysis. As shown in Fig 2, these proteins are also found to be overrepresented in DLT individuals, but not in OLT individuals. TTR and the C-reactive protein, a prototypic acute phase protein, levels do not present any significative difference between DLT and OLT individuals.

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