Transthyretin amyloid aggregate (TTR amyloid aggregate (TTR aggregate))

Transthyretin amyloid aggregates are highly ordered, β-sheet-rich fibrillar protein deposits formed from the misfolding and aggregation of transthyretin (TTR), a tetrameric plasma protein responsible for transport of thyroxine and retinol-binding protein. Under pathological conditions, such as destabilizing mutations or aging, TTR tetramers dissociate into monomers, which then misfold and self-assemble into toxic oligomers and amyloid fibrils. These amyloid aggregates accumulate in multiple organs, leading to tissue dysfunction and a group of diseases collectively known as transthyretin amyloidoses (including familial amyloid polyneuropathy and senile systemic amyloidosis). Therapies target the stabilization of native TTR tetramers, inhibition of aggregate formation, or knockdown of TTR protein expression to prevent new amyloid deposition. TTR amyloid deposits can be detected using histochemistry, mass spectrometry, or imaging and are important both as a disease biomarker and a therapeutic target.

Other names

transthyretin fibrilTTR amyloid fibrilTTR aggregateATTR amyloidtransthyretin-derived amyloid aggregate

Tetramer stabilization to prevent dissociation (e.g., tafamidis, diflunisal); Inhibition of amyloid fibril elongation (peptide aggregation inhibitors); Reduction of TTR synthesis at RNA level (e.g., patisiran, inotersen; these lower amyloid formation indirectly by reducing TTR levels); Competitive binding to thyroxine-binding site (prevents conformational change)