Transthyretin Misfolding, A Fatal Structural Pathogenesis Mechanism

Abstract

Transthyretin (TTR) is an essential transporter of a thyroid hormone and a holo-retinol binding protein, found abundantly in human plasma and cerebrospinal fluid. In addition, this protein is infamous for its amyloidogenic propensity, causing various amyloidoses in humans, such as senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. It has been known for over two decades that decreased stability of the native tetrameric conformation of TTR is the main cause of these diseases. Yet, mechanistic details on the amyloidogenic transformation of TTR were not clear until recent multidisciplinary investigations on various structural states of TTR. In this review, we discuss recent advancements in the structural understanding of TTR misfolding and amyloidosis processes. Special emphasis has been laid on the observations of novel structural features in various amyloidogenic species of TTR. In addition, proteolysis-induced fragmentation of TTR, a recently proposed mechanism facilitating TTR amyloidosis, has been discussed in light of its structural consequences and relevance to acknowledge the amyloidogenicity of TTR.

A Brief Journey through Protein Misfolding in Transthyretin Amyloidosis (ATTR Amyloidosis)

“…Annular oligomers are composed of double stacks of octamers that tend to convert into spheroidal oligomers consisting of 8–18 monomers [ 34 ]. Aggregates of TTR mutant oligomers exhibit higher molecular weight than wild-type aggregates [ 4 ].…”

“…Seeding relies on the addition of preformed compounds, while nucleation implies the birth of new ones. Many oligomers have been identified in the early stages of fibrillation, serving as a precursor of amyloid nucleation [ 34 ]. Electron microscopic studies have shown amorphous electron-dense materials around microvessels and the subperineural space in addition to speckles or fine fibrillar-structures within the periphery, which may be the core of the amyloid fibrils [ 2 ].…”

“…Different proteases have been implicated in the production of TTR fragments, such as plasmin, which showed TTR proteolysis on WT-TTR and amyloidogenic variants, or subtilisin, which is a serine protease from a nonpathogenic microbe in the gut, Bacillus subtilis [ 37 ]. The increased gut permeability occurring during aging could increase subtilisin levels into the human plasma, contributing to the pathogenesis of WT-cardiac amyloidosis [ 7 , 34 , 37 ].…”

In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis

“…Despite it is widely accepted that tetramer destabilization is a rate-limiting step for the development of amyloid fibrils [9][10][11][12], TTR proteolysis has been increasingly recognized as another mechanism driving TTR amyloid formation. Several studies reported the existence of different TTR amyloid deposits in a range of tissues.…”

Molecular Mechanisms of Cardiac Amyloidosis

“…Recently, proteolysis-induced fragmentation of TTR has been proposed as a mechanism facilitating the development of ATTR amyloidosis [ 36 ]. Amyloid deposits are classified into type A, which consists of a mixture of cleaved TTR and full-length TTR, and type B, which consists only of full-length TTR.…”