title: Transthyretin Amyloidosis: Chaperone Concentration Changes and Increased Proteolysis in the Pathway to Disease.
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.
authors.affiliation: Centro de Química e Bioquímica, FCUL, Campo Grande, Lisboa, Portugal.
authors.forename: Gonçalo
authors.initials: G
authors.lastname: da Costa
authors.affiliation: Centro de Química e Bioquímica, FCUL, Campo Grande, Lisboa, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ribeiro-Silva
authors.affiliation: Centro de Química e Bioquímica, FCUL, Campo Grande, Lisboa, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Ribeiro
authors.affiliation: Centro de Química e Bioquímica, FCUL, Campo Grande, Lisboa, Portugal.
authors.forename: Samuel
authors.initials: S
authors.lastname: Gilberto
authors.affiliation: Instituto de Tecnologia Química e Biológica, Av. da República Estação Agronómica Nacional, Oeiras, Portugal.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Gomes
authors.affiliation: Centro de Química e Bioquímica, FCUL, Campo Grande, Lisboa, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Ferreira
authors.affiliation: Unidade de Transplantação, Hospital Curry Cabral, Lisboa, Portugal.
authors.forename: Élia
authors.initials: É
authors.lastname: Mateus
authors.affiliation: Unidade de Transplantação, Hospital Curry Cabral, Lisboa, Portugal.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Barroso
authors.affiliation: Instituto de Tecnologia Química e Biológica, Av. da República Estação Agronómica Nacional, Oeiras, Portugal.
authors.forename: Ana V
authors.initials: AV
authors.lastname: Coelho
authors.affiliation: Centro de Química e Bioquímica, FCUL, Campo Grande, Lisboa, Portugal.
authors.forename: Ana Ponces
authors.initials: AP
authors.lastname: Freire
authors.affiliation: Centro de Química e Bioquímica, FCUL, Campo Grande, Lisboa, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordeiro
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D028227:Amyloid Neuropathies, Familial / Q000097:blood / Q000378:metabolism*; D001798:Blood Proteins / Q000737:chemistry; D016022:Case-Control Studies; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D008969:Molecular Sequence Data; D059748:Proteolysis; D040901:Proteomics; D017386:Sequence Homology, Amino Acid; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D001798:Blood Proteins; D018832:Molecular Chaperones