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.

Keywords: amyloid inhibitors; amyloidosis; mechanism of disease; therapy; transthyretin.

Figure 1

Human transthyretin (TTR) tetramer structure in complex with two thyroxine molecules (stick models) bound in the central hydrophobic channel, from PDB 2ROX (Wojtczak et al., 1996). TTR subunits are colored differently (blue, green, brown and yellow). Figure made with PyMOL (DeLano, 2005).

Figure 2

Mechanisms-driving TTR amyloidogenesis and different therapeutic targets for the treatment of ATTR amyloidosis. Tetramer destabilization is widely accepted as a rate-limiting step for the development of amyloid fibrils. However, TTR proteolysis has been increasingly suggested as an alternative mechanism contributing to amyloid formation. Several pharmacological agents have been implicated in the treatment of ATTR amyloidosis, from inhibitors of TTR synthesis, tetramer stabilizers, inhibitors of amyloid formation and even disruptors of formed fibrils. The modulation of TTR proteolysis may also be helpful for the treatment of ATTR amyloidosis. Despite the protease responsible for this process has not yet been identified, its specific cleavage patterns suggest that it could be a trypsin-like serine protease. Accordingly, pharmacological molecules targeting lysine residues, as well as physiological serine protease inhibitors may be act as modulators of TTR proteolysis, consequently inhibiting amyloid formation.