title: Beyond genetic factors in familial amyloidotic polyneuropathy: protein glycation and the loss of fibrinogen's chaperone activity.
abstract: Familial amyloidotic polyneuropathy (FAP) is a systemic conformational disease characterized by extracellular amyloid fibril formation from plasma transthyretin (TTR). This is a crippling, fatal disease for which liver transplantation is the only effective therapy. More than 80 TTR point mutations are associated with amyloidotic diseases and the most widely accepted disease model relates TTR tetramer instability with TTR point mutations. However, this model fails to explain two observations. First, native TTR also forms amyloid in systemic senile amyloidosis, a geriatric disease. Second, age at disease onset varies by decades for patients bearing the same mutation and some mutation carrier individuals are asymptomatic throughout their lives. Hence, mutations only accelerate the process and non-genetic factors must play a key role in the molecular mechanisms of disease. One of these factors is protein glycation, previously associated with conformational diseases like Alzheimer's and Parkinson's. The glycation hypothesis in FAP is supported by our previous discovery of methylglyoxal-derived glycation of amyloid fibrils in FAP patients. Here we show that plasma proteins are differentially glycated by methylglyoxal in FAP patients and that fibrinogen is the main glycation target. Moreover, we also found that fibrinogen interacts with TTR in plasma. Fibrinogen has chaperone activity which is compromised upon glycation by methylglyoxal. Hence, we propose that methylglyoxal glycation hampers the chaperone activity of fibrinogen, rendering TTR more prone to aggregation, amyloid formation and ultimately, disease.
authors: Centro de Química e Bioquímica, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal.
authors: Gonçalo
authors: G
authors: da Costa
authors: Ricardo A
authors: RA
authors: Gomes
authors: Ana
authors: A
authors: Guerreiro
authors: Élia
authors: É
authors: Mateus
authors: Estela
authors: E
authors: Monteiro
authors: Eduardo
authors: E
authors: Barroso
authors: Ana V
authors: AV
authors: Coelho
authors: Ana Ponces
authors: AP
authors: Freire
authors: Carlos
authors: C
authors: Cordeiro
mesh_terms: D000328:Adult; D028227:Amyloid Neuropathies, Familial / Q000235:genetics*; D015153:Blotting, Western; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D005340:Fibrinogen / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000378:metabolism*; D009952:Ornithine / Q000031:analogs & derivatives / Q000378:metabolism; D011228:Prealbumin / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D011743:Pyrimidines / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D055815:Young Adult
chemical_list: D018832:Molecular Chaperones; D011228:Prealbumin; D011743:Pyrimidines; C107313:argpyrimidine; D005340:Fibrinogen; D009952:Ornithine