The amyloidogenic potential of transthyretin variants correlates with their tendency to aggregate in solution

FEBS Letters
A QuintasR M Brito

Abstract

Amyloid fibril formation and deposition are the basis for a wide range of diseases, including spongiform encephalopathies, Alzheimer's and familial amyloidotic polyneuropathies. However, the molecular mechanisms of amyloid formation are still poorly characterised. In certain forms of familial amyloidotic polyneuropathy (FAP), the amyloid fibrils are mostly constituted by variants of transthyretin (TTR). V30M-TTR is the most frequent variant, and L55P-TTR is the variant associated with the most aggressive form of amyloidosis. Here, we report gel filtration chromatography experiments to characterise the aggregation states of WT-, V30M-, L55P-TTR and a non-amyloidogenic variant, T119M-TTR, in solution, at nearly physiological pH. These studies show that all four protein tetramers dissociate to monomer upon dilution, in the submicromolar range, at pH 7.0. The amyloidogenic proteins V30M- and L55P-TTR show a complex equilibrium between monomers, tetramers and high molecular weight aggregate species. These aggregates dissociate directly to monomer upon dilution. This study shows that the tendency to form aggregates among the four studied proteins correlates with their known amyloidogenic potential. Thus, the amyloidogenic mutations c...Continue Reading

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