THE AMYLOIDOGENIC POTENTIAL OF TRANSTHYRETIN VARIANTS CORRELATES WITHTHEIR TENDENCY TO AGGREGATE IN SOLUTION

Amyloid fibril formation and deposition are the basis for a aide range of diseases, including spongiform encephalopathies, Alzheimer's and f amilial amyloidotic polyneuropathies. However, the molecular mechanism s of amyloid formation are still poorly characterised. In certain form s of familial amyloidotic polyneuropathy (FAP), the amyloid fibrils ar e mostly constituted by variants of transthyretin (TTR), V30M-TTR is t he most frequent variant, and L55P-TTR is the variant associated with the most aggressive form of amyloidosis. Here, me report gel filtratio n chromatography experiments to characterise the aggregation states of WT-, V30M-, L-55P-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 submicr omolar range, at pH 7.0, The amyloidogenic proteins V30M- and L55P-TTR show a complex equilibrium between monomers, tetramers and high molec ular weight aggregate species, These aggregates dissociate directly to monomer upon dilution, This study shows that the tendency to form agg regates among the four studied proteins correlates with their known am yloidogenic potential, Thus, the amyloidogenic mutations could perturb the structure and/or stability of the monomeric species leading initi ally to the formation of soluble aggregates and at a later stage to in soluble amyloid fibrils. (C) 1997 Federation of European Biochemical S ocieties.