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: name-transports thyroxine and retinol.
The liver secretes TTR into the blood, and the choroid plexus secretes TTR into the cerebrospinal fluid.
TTR is primarily synthesized by hepatocytes, although approximately 5% is produced by retinal and choroid plexus epithelial cells.
Transthyretin protein is encoded by the TTR gene located on the 18th chromosome.
It functions in concert with two other thyroid hormone-binding proteins in the serum:
In cerebrospinal fluid TTR is the primary carrier of T4.
TTR also acts as a carrier of retinol (vitamin A) through its association with retinol-binding protein (RBP) in the blood and the CSF.
Less than 1% of TTR’s T4 binding sites are occupied in blood.
TTRs dissociation, misfolding and aggregation which leads to the degeneration of post-mitotic tissue.
Numerous other small molecules bind in the thyroxine binding sites, including many natural products, such as resveratrol, drugs Tafamidis,or Vyndaqel, diflunisal, flufenamic acid and toxicants, PCB.
TTR is a 55kDa structure 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.
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).
ATTR amyloidosis presents as wild type, ATTR amyloidosis, caused by age related instability of the TTR proteins, or as variant A TTR amyloidosis caused by abnormal TTR proteins due to a genetic variant.
ATTR variant amyloidosis is inherited in an autosomal dominant pattern with a variable penetrance, and up to 50% of patients with ATTR variant have no family history of ammoidosis.
ATTR amyloidosis results in amyloid fibril accumulation in multiple organs, most commonly affecting the peripheral and autonomic nervous systems and the heart.
Neurologic effects of ATTR amyloidosis include symmetric neuropathy, which may cause paresthesia pain, weakness, and imbalance and autonomic dysfunction, such as orthostatic, hypotension, early satiety and erectile dysfunction.
With cardiac ATTR amyloidosis patients present with heart failure with preserved ejection fraction, and some develop atrial fibrillation and angina.
More than 140 variants of ATTR have been described.
Approximately 3% of black individuals are carriers of the VAL142LLE variant.
Other manifestations of ATTR variant include lumbar spinal stenosis, and rarely stroke, dementia, seizures, and headaches.
TTR tetramer dissociation is known to be rate-limiting for amyloid fibril formation.
The average diagnostic delay for ATTR amyloidosis is four years after symptom onset.
While systemic amyloidosis requires tissue confirmation of Congo red extracellular deposits that show apple green birefringence under polarized light microscopy ATTR cardiac amyloidosis diagnosis can be made on the base of increased cardiac update on radionucleotide scanning.
Radiotracer myocardial uptake on bone scan is more than 99% sensitive and 86% specific for the diagnosis of cardiac ATTR amyloidosis.
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.
While wild type TTR can dissociate, misfold, and aggregate, leading to 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 familial amyloid polyneuropathy.
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 familial amyloid cardiomyopathy.
Senile systemic amyloidosis (SSA) is estimated to affect over 25% of the population over age 80.
Severity of disease varies greatly by mutation, with some mutations causing disease in the first or second decade of life, and others being more benign.
Deposition of TTR amyloid is generally extracellular.
TTR deposits are also observed within the cardiomyocytes of the heart.
Transthyretin is a negative acute phase protein.
Treatment of familial (hereditary) TTR amyloid disease has historically relied on liver transplantation as a crude form of gene therapy.
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.
TTR binds to the beta-amyloid protein, thereby preventing beta-amyloid’s natural tendency to accumulate into the plaques associated with the early stages of Alzheimer’s disease.
Preventing plaque formation is thought to enable a cell to rid itself of this otherwise toxic protein form and, thus, help prevent and maybe even treat the disease.
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.
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.