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Transthyretin (TTR) amyloidosis is a progressive disease characterized by an abrupt aggregation of misfolded protein in multiple organs and tissues TTR is a tetrameric protein expressed in the liver and choroid plexus. Protein misfolding triggers monomerization of TTR tetramers. Next, monomers assemble forming oligomers and fibrils. Although the secondary structure of TTR fibrils is well understood, there is very little if anything is known about the structural organization of TTR oligomers. To end this, we used nano‐infrared spectroscopy, also known as atomic force microscopy infrared (AFM‐IR) spectroscopy. This emerging technique can be used to determine the secondary structure of individual amyloid oligomers and fibrils. Using AFM‐IR, we examined the secondary structure of TTR oligomers formed at the early (3–6 h), middle (9–12 h), and late (28 h) of protein aggregation. We found that aggregating, TTR formed oligomers (Type 1) that were dominated by α‐helix (40%) and β‐sheet (~30%) together with unordered protein (30%). Our results showed that fibril formation was triggered by another type of TTR oligomers (Type 2) that appeared at 9 h. These new oligomers were primarily composed of parallel β‐sheet (55%), with a small amount of antiparallel β‐sheet, α‐helix, and unordered protein. We also found that Type 1 oligomers were not toxic to cells, whereas TTR fibrils formed at the late stages of protein aggregation were highly cytotoxic. These results show the complexity of protein aggregation and highlight the drastic difference in the protein oligomers that can be formed during such processes. [ABSTRACT FROM AUTHOR]

Transthyretin (TTR) is a small, β-sheet-rich tetrameric protein that transports thyroid hormone thyroxine and retinol. Phospholipids, including phosphatidic acid (PA), can uniquely alter the stability of amyloidogenic proteins. However, the role of PA in TTR aggregation remains unclear. In this study, we investigated the effect of saturation of fatty acids (FAs) in PA on the rate of TTR aggregation. We also reveal the extent to which PAs with different length and saturation of FAs altered the morphology and secondary structure of TTR aggregates. Our results showed that TTR aggregation in the equimolar presence of PAs with different length and saturation of FAs yielded structurally and morphologically different fibrils compared to those formed in the lipid-free environment. We also found that PAs drastically lowered the toxicity of TTR aggregates formed in the presence of this phospholipid. These results shed light on the role of PA in the stability of TTR and transthyretin amyloidosis. [Display omitted] • The length and saturation of fatty acids in phosphatidic acid uniquely alter the rate of transthyretin aggregation. • PAs drastically lower the toxicity of TTR aggregates formed in the presence of this phospholipid. • The length and saturation of fatty acids in phosphatidic acid change the secondary structure of transthyretin fibrils. [ABSTRACT FROM AUTHOR]