The role of protein oxidation in the onset of the transthyretin amyloidoses

Abstract

The transthyretin (TTR) amyloidoses are a subset of protein misfolding diseases characterized by the age‐dependent deposition of amyloid fibrils, derived from either wild type or mutant forms of the plasma protein TTR. Although it is clear that age is a major risk factor for the development of the TTR and other systemic amyloidoses, there are few studies addressing the molecular mechanisms responsible for the apparent effect of aging.There is a general increase in the concentrations of oxidation products of proteins, lipids and DNA associated with aging. We hypothesize that an increase in TTR oxidation with age predisposes to TTR aggregation in vivo. We have produced oxidized forms of wild‐type TTR similar to those reported to be present in human plasma. Chaotrope‐mediated denaturation/renaturation experiments showed that modified forms of TTR, including those with oxidized methionines and cysteines and those with carbonylated amino acids displayed reduced in vitro stability relative to native non‐oxidized TTR. The modified TTRs also had differential propensity for amyloid fibril formation with respect to native TTR. Sera from mice transgenic for a wild‐type human TTR gene show increased degrees of TTR carbonylation with aging. The greater proportion of circulating oxidized TTR seen in the older mice with its lower stability, may play a role in the development and onset of the senile wild type TTR associated amyloidosis. (This work is supported by 1R01AG032285 NIH/NIA)