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Serum protein related to amyloid diseases

Transthyretin (TTR or TBPA) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine (T4) and retinol to the liver. This is how transthyretin gained its name: transports thyroxine and retinol. The liver secretes TTR into the blood, and the choroid plexus secretes TTR into the cerebrospinal fluid. TTR was originally called prealbumin (or thyroxine binding prealbumin) because it migrated faster than albumin on electrophoresis gels. Prealbumin was felt to be a misleading name, it is not a synthetic precursor of albumin. The alternative name TTR was proposed by DeWitt Goodman in 1981. Transthyretin protein is encoded by the TTR gene located on the 18th chromosome.

TTR is a 55kDa homotetramer with a dimer of dimers quaternary structure that is synthesized in the liver, choroid plexus and retinal pigment epithelium for secretion into the bloodstream, cerebrospinal fluid and the eye, respectively. Each monomer is a 127 residue polypeptide rich in beta sheet structure. Association of two monomers via their edge beta strands forms an extended beta sandwich. Further association of two of these dimers in a face to face fashion produces the homotetrameric structure and creates the two thyroxine binding sites per tetramer. This dimer dimer interface, comprising the two T4 binding sites, is the weaker dimer dimer interface and is the one that comes apart first in the process of tetramer dissociation.

TTR misfolding and aggregation is known to be associated with amyloid diseases including wild type transthyretin amyloidosis, hereditary transthyretin amyloidosis, familial amyloid polyneuropathy (FAP), and familial amyloid cardiomyopathy (FAC). TTR tetramer dissociation is known to be rate limiting for amyloid fibril formation. However, the monomer also must partially denature in order for TTR to be mis assembly competent, leading to a variety of aggregate structures, including amyloid fibrils. At least 114 disease causing mutations in this gene have been discovered. While wild type TTR can dissociate, misfold, and aggregate, leading to SSA (senile systemic amyloidosis), point mutations within TTR are known to destabilize the tetramer composed of mutant and wild type TTR subunits, facilitating more facile dissociation and/or misfolding and amyloidogenesis. A replacement of valine by methionine at position 30 (TTR V30M) is the mutation most commonly associated with FAP. A position 122 replacement of valine by isoleucine (TTR V122I) is carried by 3.9% of the African American population, and is the most common cause of FAC. Because TTR is primarily produced in the liver, replacement of a liver containing a mutant TTR gene with a normal gene is able to reduce the mutant TTR levels in the body to < 5% of pretransplant levels. Certain mutations, however, cause CNS amyloidosis, and due to their production by the choroid plexus, the CNS TTR amyloid diseases do not respond to gene therapy mediated by liver transplantation. In 2011, the European Medicines Agency approved tafamidis (Vyndaqel) for the amelioration of FAP. and/or the peripheral nervous system and/or the heart. There is now strong genetic and pharmacologic data (see European Medicines Agency website for the tafamidis clinical trial results) indicating that the process of amyloid fibril formation leads to the degeneration of post mitotic tissue causing FAP and likely FAC and SSA. Evidence points to the oligomers generated in the process of amyloidogenicity leading to the observed proteotoxicity. Transthyretin level in cerebrospinal fluid has also been found to be lower in patients with some neurobiological disorders such as schizophrenia. The reduced level of transthyretin in the CSF may indicate a lower thyroxine transport in brains of patients with schizophrenia. Transthyretin is known to contain a Gla domain, and thus be dependent for production on post translational modification requiring vitamin K, but the potential link between vitamin k status and thyroid function has not been explored. Because transthyretin is made in part by the choroid plexus, it can be used as an immunohistochemical marker for choroid plexus papillomas as well as carcinomas. As of March 2015, there are two ongoing clinical trials undergoing recruitment in the United States and worldwide to evaluate potential treatments for TTR amyloidosis.

Transthyretin has been shown to interact with perlecan.