HORMONE DELIVERY SYSTEMS TO THE BRAIN - TRANSTHYRETIN

This paper reviews knowledge on the structure and function and evolution of the thyroid hormone binding protein transthyretin (TTR), with particular reference to factors affecting thyroid hormone distribution and delivery to the brain. The pool of thyroid hormones critical for the biological actions of the hormones is the pool of free thyroid hormone. The size of this pool is determined for shea time periods by uptake/release of thyroid hormones into/from cell and binding/release of thyroid hormones by thyroid hormone-binding proteins. Both proportions and absolute concentrations of these proteins differ in blood plasma and cerebrospinal fluid (CSF). The most pronounced difference is found for TTR which is the only thyroid hormone-binding plasma protein synthesized in the brain. TTR is also distinct from the other two thyroid hormone-binding plasma proteins in humans by the absence of genetic deficiencies. TTR gene expression was initiated during evolution much earlier in the brain than in the liver. The structure of the domains of TTR involved in thyroxine (TR) T4 binding has been completely conserved for 350 million years. These observations point to a special functional significance of TTR in the brain. It is proposed that this is the determination of the level of free T4 in the extracellular compartment of the brain. T4 can then be converted in the brain to triiodothyronine T3 by specific deiodinases. This T3 can interact with receptors in the cell nuclei, regulating gene transcription. Synthesis and secretion of TTR by the choroid plexus and the relative enrichment of TTR in CSF (compared with the protein concentration pattern in blood plasma) lead to independent and different homeostasis of T4 in the extracellular environment of brain and body.