Development of Therapeutic Strategies for the Transthyretin Amyloidoses

A Complex Equilibrium among Partially Unfolded Conformations in Monomeric Transthyretin

“…TTR can misfold and selfassemble into amyloid aggregates, leading to tissue dysfunction. 1−3 This process is linked to a series of sporadic and inherited pathological conditions, 2,3 including senile systemic amyloidosis, familial amyloid cardiomyopathy, familial amyloid polyneuropathy, and leptomeningeal amyloidosis. In these disorders, TTR aggregates in specific tissues, leading to a welldefined diseased phenotype probably caused by the formation of oligomeric species and subsequently of the amyloid and amorphous deposits.…”

“…Despite its biological function as a carrier protein, TTR has been the subject of intense studies for more than 30 years because of its pathogenic properties. TTR can misfold and self-assemble into amyloid aggregates, leading to tissue dysfunction. − This process is linked to a series of sporadic and inherited pathological conditions, , including senile systemic amyloidosis, familial amyloid cardiomyopathy, familial amyloid polyneuropathy, and leptomeningeal amyloidosis. In these disorders, TTR aggregates in specific tissues, leading to a well-defined diseased phenotype probably caused by the formation of oligomeric species and subsequently of the amyloid and amorphous deposits. − More than 100 mutations have been linked to TTR pathologies, and a general trend is that the more the mutation destabilizes the quaternary structure, the more pathological the variant is. ,, The stability of the tetrameric structure has been linked to the kinetics of tetramer dissociation.…”