Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases

Abstract

Transthyretin (TTR) is a tetrameric protein transporting hormones in the plasma and brain, which has many other activities that have not been fully acknowledged. TTR is a positive indicator of nutrition status and is negatively correlated with inflammation. TTR is a neuroprotective and oxidative-stress-suppressing factor. The TTR structure is destabilized by mutations, oxidative modifications, aging, proteolysis, and metal cations, including Ca2+. Destabilized TTR molecules form amyloid deposits, resulting in senile and familial amyloidopathies. This review links structural stability of TTR with the environmental factors, particularly oxidative stress and Ca2+, and the processes involved in the pathogenesis of TTR-related diseases. The roles of TTR in biomineralization, calcification, and osteoarticular and cardiovascular diseases are broadly discussed. The association of TTR-related diseases and vascular and ligament tissue calcification with TTR levels and TTR structure is presented. It is indicated that unaggregated TTR and TTR amyloid are bound by vicious cycles, and that TTR may have an as yet undetermined role(s) at the crossroads of calcification, blood coagulation, and immune response.

Transthyretin Amyloid Cardiomyopathy: Impact of Transthyretin Amyloid Deposition in Myocardium on Cardiac Morphology and Function

“…TTR non-fibrillar aggregates induce a cytotoxic response that involves mitochondrial dysfunction, endoplasmic reticulum stress, and dysregulation of the Ca 2+ balance. Consequently, these cytotoxic responses may result in ROS accumulation and inflammation progression [ 17 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ].…”

“…In ATTR-CM, fibrillogenesis requires the dissociation of the TTR homotetrameric structure into misfolded monomers that self-assemble into soluble oligomeric species, which then misassemble into amyloid fibrils and deposit in the myocardium [ 4 , 5 , 6 , 14 , 15 ]. Previous studies have shown that TTR amyloid deposition is closely related to reactive oxygen species (ROS) accumulation and cell apoptosis [ 16 , 17 ]. Several clinical studies have reported that both stabilizers of TTR homotetramers and RNA interference therapies inhibiting TTR synthesis prevent the progression of ATTR-CM [ 15 , 18 , 19 , 20 , 21 ].…”

Apolipoprotein Signature of HDL and LDL from Atherosclerotic Patients in Relation with Carotid Plaque Typology: A Preliminary Report

“…Particularly, some proteins that might contribute to increase cardiovascular risk in patients with soft plaque showed higher expression levels in HDL "soft" compared to "hard", including complement factors C3 and C4, which have been described to promote atherosclerosis [63]; integrins, which are a class of proteins that may mediate the recruitment of inflammatory cells to atherosclerotic plaques [64]; prenylcysteine oxidase 1 [65], which is a pro-oxidant enzyme; transthyretin [66]; and lipopolysaccharide-binding protein, which has been previously evidenced to play a role in atherosclerosis development [67] and cardiovascular mortality [68]. Moreover, some SAA proteins (SAA1, SAA2, and SAA4) were found up-regulated in the HDL "soft" group but down-regulated, with the exception of SAA1, in the LDL "soft" group.…”

The Journey of Human Transthyretin: Synthesis, Structure Stability, and Catabolism

“…TTR stability can be negatively affected also by ageing, metal cations (especially Ca 2+ ), and oxidative modifications [ 90 ] at the free cysteine residue in position 10 (Cys10), see later in the text.…”

“…The dissociation of TTR tetramers results in partially unfolded monomers assembling into aggregates with various quaternary structures [ 90 ]. TTR aggregates undergo structural rearrangements forming cytotoxic oligomers.…”