Abstract
Transthyretin (TTR) amyloidoses (ATTR amyloidosis) are diseases associated with transthyretin (TTR) misfolding, aggregation and extracellular deposition in tissues as amyloid. Clinical manifestations of the disease are variable and include mainly polyneuropathy and/or cardiomyopathy. The reasons why TTR forms aggregates and amyloid are related with amino acid substitutions in the protein due to mutations, or with environmental alterations associated with aging, that make the protein more unstable and prone to aggregation. According to this model, several therapeutic approaches have been proposed for the diseases that range from stabilization of TTR, using chemical chaperones, to clearance of the aggregated protein deposited in tissues in the form of oligomers or small aggregates, by the action of disruptors or by activation of the immune system. Interestingly, different studies revealed that curcumin presents anti-amyloid properties, targeting multiple steps in the ATTR amyloidogenic cascade. The effects of curcumin on ATTR amyloidosis will be reviewed and discussed in the current work in order to contribute to knowledge of the molecular mechanisms involved in TTR amyloidosis and propose more efficient drugs for therapy.
Highlights
Transthyretin (TTR) is a plasma protein that functions mainly as a transporter for thyroid hormones, in particular thyroxine (T4) and retinol in complex with retinol binding protein (RBP) [1]
In the cerebrospinal fluid (CSF), TTR interacts with neuropeptide Y (NPY) [5] and with amyloid-β (Aβ) peptide, indicating a neuroprotective role for TTR in the central nervous system [6,7]
The predominance of the β-chain structure in the polypeptide chains of the TTR tetramer, and its organization as β-sheets contribute to the intrinsic amyloid potential of the protein, leading to aggregation, fibril formation, and deposition under specific conditions, originating transthyretin amyloidosis (ATTR amyloidosis)
Summary
Transthyretin (TTR) is a plasma protein that functions mainly as a transporter for thyroid hormones, in particular thyroxine (T4) and retinol (vitamin A) in complex with retinol binding protein (RBP) [1]. TTR is known to interact with other protein ligands and small molecules, either natural or synthetic compounds. The four monomers in the tetramer interact with each other through non-covalent bonds, establishing a strong interaction between two monomers, forming dimers that assemble as a tetramer originating a central hydrophobic channel limited by amino acids from both dimers. This channel has two similar binding sites for thyroxine molecules [23]. The predominance of the β-chain structure in the polypeptide chains of the TTR tetramer, and its organization as β-sheets contribute to the intrinsic amyloid potential of the protein, leading to aggregation, fibril formation, and deposition under specific conditions, originating transthyretin amyloidosis (ATTR amyloidosis)
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