Modulation of the Mechanisms Driving Transthyretin Amyloidosis

Abstract

Transthyretin (TTR) amyloidoses are systemic diseases associated with TTR aggregation and extracellular deposition in tissues as amyloid. The most frequent and severe forms of the disease are hereditary and associated with amino acid substitutions in the protein due to single point mutations in the TTR gene (ATTRv amyloidosis). However, the wild type TTR (TTR wt) has an intrinsic amyloidogenic potential that, in particular altered physiologic conditions and aging, leads to TTR aggregation in people over 80 years old being responsible for the non-hereditary ATTRwt amyloidosis. In normal physiologic conditions TTR wt occurs as a tetramer of identical subunits forming a central hydrophobic channel where small molecules can bind as is the case of the natural ligand thyroxine (T4). However, the TTR amyloidogenic variants present decreased stability, and in particular conditions, dissociate into partially misfolded monomers that aggregate and polymerize as amyloid fibrils. Therefore, therapeutic strategies for these amyloidoses may target different steps in the disease process such as decrease of variant TTR (TTRv) in plasma, stabilization of TTR, inhibition of TTR aggregation and polymerization or disruption of the preformed fibrils. While strategies aiming decrease of the mutated TTR involve mainly genetic approaches, either by liver transplant or the more recent technologies using specific oligonucleotides or silencing RNA, the other steps of the amyloidogenic cascade might be impaired by pharmacologic compounds, namely, TTR stabilizers, inhibitors of aggregation and amyloid disruptors. Modulation of different steps involved in the mechanism of ATTR amyloidosis and compounds proposed as pharmacologic agents to treat TTR amyloidosis will be reviewed and discussed.

The Transthyretin/Oleuropein Aglycone Complex: A New Tool against TTR Amyloidosis

“…Among these molecules, natural flavonoids, such as EGCG, do not bind at the T4 binding site and stabilize the tetrameric structure by a stable interaction at the surface of each TTR monomer [ 28 ]. In particular, EGCG binds at the dimer–dimer interface, with a resulting effect similar to that of a cross-linker [ 41 ]. Our results indicate that OleA binds both at the main funnel and at the hydrophobic surfaces of TTR.…”

Extracellular Vesicles Contribute to the Metabolism of Transthyretin Amyloid in Hereditary Transthyretin Amyloidosis

“…In amyloidosis, the aggregation of the major causative protein is promoted on the surface of the EV membrane, which is assumed to alleviate the pathological conditions ( Yuyama et al, 2012 ; Falker et al, 2016 ). TTR variant, as a major causative protein, causes TTR aggregation and deposition on specific tissues ( Bezerra et al, 2020 ). In this study, we showed via atomic force microscopy that TTR aggregation is promoted by EVs and that TTR multimerizes on the surface of EVs.…”

Transthyretin Misfolding, A Fatal Structural Pathogenesis Mechanism

“…In recent years, advancements have been made in understanding the structural features of non-native and misfolded monomeric, oligomeric, and aggregated TTR species, employing various interdisciplinary techniques, such as solution/solid-state NMR spectroscopy, force spectroscopy, mass spectrometry, cryo-EM, and computational modeling. In particular, the proteolysis-induced amyloidosis mechanism of TTR has attracted much attention in recent years, and various structural studies have revealed the mechanistic details of this amyloidosis process [ 95 ]. Along with recent boosts in multidisciplinary methodology developments, further improvements are soon expected in understanding of TTR amyloidosis pathology and developing an even more effective therapeutic strategy against this disease.…”