Cell and molecular biology of transthyretin and thyroid hormones

Advances in four areas of transthyretin (TTR) research result in this being a timely review. Developmental studies have revealed that TTR is synthesized in all classes of vertebrates during development. This leads to a new hypothesis on selection pressure for hepatic TTR synthesis during development only, changing the previous hypotheses from "onset" of hepatic TTR synthesis in adulthood to "maintaining" hepatic TTR synthesis into adulthood. Evolutionary studies have revealed the existence of TTR-like proteins (TLPs) in nonvertebrate species and elucidated some of their functions. Consequently, TTR is an excellent model for the study of the evolution of protein structure, function, and localization. Studies of human diseases have demonstrated that TTR in the cerebrospinal fluid can form amyloid, but more recently there has been recognition of the roles of TTR in depression and Alzheimer's disease. Furthermore, amyloid mutations in human TTR that are the normal residues in other species result in cardiac deposition of TTR amyloid in humans. Finally, a revised model for TTR-thyroxine entry into the cerebrospinal fluid via the choroid plexus, based on data from studies in TTR null mice, is presented. This review concentrates on TTR and its thyroid hormone binding, in development and during evolution, and summarizes what is currently known about TLPs and the role of TTR in diseases affecting the brain.