The Transthyretin Amyloidoses: From Delineating the Molecular Mechanism of Aggregation Linked to Pathology to a Regulatory-Agency-Approved Drug

Abstract

Transthyretin (TTR) is one of the many proteins that are known to misfold and aggregate (i.e., undergo amyloidogenesis) in vivo. The process of TTR amyloidogenesis causes nervous system and/or heart pathology. While several of these maladies are associated with mutations that destabilize the TTR native quaternary and/or tertiary structure, wild type TTR amyloidogenesis also leads to the degeneration of post-mitotic tissue. Over the past twenty years, much has been learned about the factors that influence the propensity of TTR to aggregate. This biophysical information led to the development of a therapeutic strategy, termed “kinetic stabilization”, to prevent TTR amyloidogenesis. This strategy afforded the drug, tafamidis (trade name: Vyndaqel®), which was recently approved by the European Medicines Agency for the treatment of Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP), a common familial TTR amyloid disease. Tafamidis is the first, and currently the only, medication approved to treat TTR-FAP. Here we review the biophysical basis for the kinetic stabilization strategy and the structure-based drug design effort that led to this first-in-class pharmacologic agent.

Multiple Substitutions of Methionine 129 in Human Prion Protein Reveal Its Importance in the Amyloid Fibrillation Pathway

“…6) (48), this could be an exploitable avenue for classical drug discovery endeavors. Similar small molecule kinetic stabilization of the native state has been exploited fruitfully to avoid misfolding of the tetrameric protein transthyretin (57,58). FIGURE 6.…”

Cardiac amyloidosis in a heart transplant patient - A case report and retrospective analysis of amyloidosis evolution

“…The age-dependent disease manifestation may depend on the activity of stress-responsive signalling pathways. Their activity decreases with increasing age and enable the occurrence of misfolded, potentially amyloidogenic peptides and proteins (12). Heat shock proteins (HSP) are involved in these pathways and processes (13).…”

Expanding Proteostasis by Membrane Trafficking Networks

“…In addition to the more than 7000 rare misfolding disorders defective in folding and trafficking responsible for disease, their are numerous examples of mutations in the CTF TPN components that affect trafficking and contribute to a diversity of inherited diseases. Common misfolding diseases affected by the TPN include, among others, neurodegenerative (Alzheimer's, Parkinson's, Huntington's) (Ong and Kelly 2011) and systemic (Johnson et al 2012) amyloid diseases, chronic obstructive pulmonary disease (COPD) (Bodas et al 2010;, type II diabetes (Scheuner and Kaufman 2008;Rowland et al 2011;Westermark et al 2011), cancer Trepel et al 2010), and cystic fibrosis ). An understanding of the mechanisms that the cell uses to continuously adjust the function of the PN and the TPN in the context of the proteostasis cloud (Fig.…”