Loss of functional albumin triggers acceleration of transthyretin amyloid fibril formation in familial amyloidotic polyneuropathy

Abstract

Transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP) is characterized by systemic accumulation of amyloid fibrils caused by a point mutation in the TTR gene. Despite the urgent need for alternative therapeutic strategies, the pathogenesis of FAP still remains elusive. In our study reported here, we focused on albumin, the most abundant protein in plasma, and described the role of albumin in the TTR amyloid-formation process. Patients with FAP evidenced significantly decreased serum albumin levels as the disease progressed. Biacore analysis showed that albumin had a binding affinity for TTR and exhibited higher affinity for TTR amyloid than native TTR. Albumin functioning as an antioxidant effectively suppressed TTR amyloid formation. In patients with FAP, albumin was significantly oxidized as the disease progressed. Moreover, loss of functional albumin accelerated TTR deposition in analbuminemic rats possessing a human variant TTR gene. Taken together, these results indicate that albumin may have an inhibitory role in the TTR amyloid-formation process.

Serum Albumin Prevents Protein Aggregation and Amyloid Formation and Retains Chaperone-like Activity in the Presence of Physiological Ligands

“…4 and 5). This finding is consistent with the observations of others: serum albumin is a major component of the soluble HMW species formed when human plasma is exposed to shear stress (5) and preferentially binds transthyretin amyloid over the native fold (63). Experimenters investigating atrial natriuretic peptide recognized that whole serum is an effective inhibitor of atrial natriuretic peptide amyloid formation, that atrial natriuretic peptide is incorporated into a number of stable complexes in this process, and that serum albumin is the most abundant counterpart in these complexes (53).…”

“…TTR is the amyloid-forming species in the transthyretin amyloidoses, a group of systemic amyloidoses that includes familial amyloid polyneuropathy, senile systemic amyloidosis, and senile cardiac amyloidosis. Recently a group studying familial amyloid polyneuropathy observed that low serum albumin not only correlated with clinical disease progression in human patients, but that analbuminaemia led to more severe disease at a younger age in a rat model (63). Thus, TTR is a potential client protein of physiological and medical relevance.…”

Structural Stabilization of Human Transthyretin by Centella asiatica (L.) Urban Extract: Implications for TTR Amyloidosis

“…Oxidatively modified TTR reportedly influences amyloidogenicity and age of onset in senile systemic amyloidosis [16]. In addition, a decrease in serum albumin antioxidant capacity was reported to accelerate TTR amyloid deposition in FAP patients [63]. Contrariwise, administration of a potent antioxidant, carvedilol, decreased TTR deposition, and oxidative and ER stresses in a FAP animal model [64].…”

Free Thiol of Transthyretin in Human Plasma Most Accessible to Modification/Oxidation

“…The cysteine residue on TTR has been reported to be highly reactive with respect to ROS and carbon centered free-radicals. 28 Meanwhile, Cys34 in albumin is located in domain I ( Figure 5B), and is surrounded by the side chains of Pro35, Asp38, His39, Val77 and Tyr84. Moreover, the sulfur atom of Cys34 is oriented toward the interior of the protein and the sulfhydryl group of Cys34 interacts with the His39 and Tyr84 side chains, 29,30 diminishing the possible interactions between the sulfhydryl group and the other compounds.…”