Misfolding of transthyretin in vivo is controlled by the redox environment and macromolecular crowding.

ABSTRACT: Transthyretin (TTR) amyloidosis is a progressive disorder characterized by peripheral neuropathy, autonomic dysfunction, and cardiomyopathy. The precise mechanism by which TTR misfolds and forms fibrils in vivo remains incompletely understood, posing challenges to the development of effective therapeutics. In this study, we reveal that the recently identified nonnative pathological species of TTR (NNTTR), which is enriched in the plasma of ttr-val30met gene carriers, exhibits strong amyloidogenic properties, making it a promising therapeutic target. Notably, we demonstrate that NNTTR formation is dependent on an intermolecular disulfide bond and can be promoted by oxidative conditions while being effectively suppressed by reducing agents. The formation of this disulfide bond is incompatibl

SUBMITTER: Jayaweera SW 

PROVIDER: S-EPMC11732491 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature