TTR is a tetrameric protein that is present in the plasma and in the cerebrospinal fluid. This protein is involved with hormone thyroxine (T4) transport, and also facilitates retinol transport through the formation of a complex with the Retinol Binding Protein (RBP). The TTR-RBP-retinol complex thus prevents retinol loss during glomerular filtration.
The adjacent picture shows the atomic structure of TTR, where we can observe the four subunities of the protein (represented in blue, green, red and yellow) as well as the internal channel that binds thyroxine (located in the C2 axis, with one thyroxine molecule displayed in each side).
Although the mechanisms of TTR aggregation are poorly understood, it occurs in vivo, associated with the deposition of the amyloid aggregates. It seems that the TTR tetramers (squares) can dissociate to amyloidogenic monomers (#1) that, in turn, originate the amyloid fibrils (#3).
It is known that this process is strongly accelerated in acidic environments. A research group from the Federal University of Rio de Janeiro, coordinated by Prof. Debora Foguel, described, in 2000, a TTR tetramer having a non-native conformation (red circles), but still able to generate amyloid fibrils.
Each TTR subunit has 127 amino acids. More than 90 amino acids changes, in different positions, have been already reported. However, alterations are restricted to particular populations. Of those mutations found in TTR gene, a mutation changing valine at amino acid 30 to methionine (Val30Met) is the responsible for FAP type I, which affects portuguese and brazilian populations. These modifications destabilize the TTR tetramer, facilitating its dissociation and consequent aggregation, which is triggered by factors that are not completely understood. Also, the mechanisms by which these aggregates exert their toxic effects to the nervous tissue remain unknown.
Pathway of Fiber Formation/TTR Denaturation.
(1): TTR tetramer dissociates in monomers. (2): Free monomers can undergo the process of unfolding. (3): Unfolded monomers can form aggregates in experimental conditions (panel A). Panels B and C show the presence of TTR aggregates in the nerves of FAP patients (in red).
Besides FAP, another clinical manifestation related to TTR aggregation is the Familial Amyloid Cardiomyopathy (FAC), which is considered the major example of infiltrative cardiomyopathy. Some mutations in the TTR gene can trigger cardiac and peripheral nerves alterations, or be exclusively associated with cardiac involvement. Cardiac involvement is caused by the deposition of TTR in the heart, and the most common variant found in this amyloidosis is the mutation V122I, present in 3-4% of African-Americans, from both Africa and the United States. TTR-related cardiac amyloidosis is often underdiagnosed, specially when neurological involvement is absent or misdiagnosed. The onset of symptoms, that may initially be confused with other causes of cardiac dysfunction, is variable. Early diagnosis is of paramount importance. In Brazil, we recently found patients with the V112I mutation, and also described a new mutation for TTR (A19D) which causes cardiomyopathy as well.
Another amyloidosis caused by the aggregation of TTR is the Oculoleptomeningeal Amyloidosis (OA), which is a rare phenotype resulting from the deposition of aggregated TTR into the blood vessels of the leptomeninges, the optic nerve, the blood-brain barrier and the spinal cord, causing dysfunctions of the nervous system and intracranial hemorrhage. Some TTR mutants have been associated with the oculoleptomeningeal amyloidosis, among them we can include the variants A18G, A25T, V30G, G53G, G53a, L55A and P64S. Symptoms usually occur around 40 years old, and patients present with different survival times.
Also, normal TTR (WT-TTR), i.e., presenting no mutation, can aggregate, causing the Senile Systemic Amyloidosis (SSA). Patients usually have congestive heart failure and arrhythmia, and symptoms commonly appear around 70 years old. It is estimated that 25% of the population over 80 years old contain some amyloid deposits composed of WT-TTR. Recently, it was shown that the WT-TTR could also deposit into tendons and ligaments in older people.
However, SSA is still underdiagnosed, as it would be required a cardiac biopsy and the characterization of this protein in the amyloid deposits for a correct diagnosis. In this way, this disease may be routinely confused with cardiomyopathies associated with other etiologies.
|Disease||Examples of Symptoms|
|Senile Systemic Amyloidosis (SSA)||Cardiomyopathy;
Carpal tunnel syndrome.
|Familial Amyloid Polyneuropathy (FAP)||Tingling in the upper and lower limbs, as well as loss of feeling; Motor neuropathy;
Alternating diarrhea and constipation;
|Familial Amyloid Cardiomyopathy (FAC)||Increased wall and interatrial septal thickness;
|Oculoleptomeningeal Amyloidosis (OA)||Dementia;