Modeling transthyretin (TTR) amyloid diseases, from monomer to amyloid fibrils

Abstract

ATTR amyloidosis is caused by deposition of large, insoluble aggregates (amyloid fibrils) of cross-β-sheet TTR protein molecules on the intercellular surfaces of tissues. The process of amyloid formation from monomeric TTR protein molecules to amyloid deposits has not been fully characterized and is therefore modeled in this paper. Two models are considered: 1) TTR monomers in the blood spontaneously fold into a β-sheet conformation, aggregate into short proto-fibrils that then circulate in the blood until they find a complementary tissue where the proto-fibrils accumulate to form the large, insoluble amyloid fibrils found in affected tissues. 2) TTR monomers in the native or β-sheet conformation circulate in the blood until they find a tissue binding site and deposit in the tissue or tissues forming amyloid deposits in situ. These models only differ on where the selection for β-sheet complementarity occurs, in the blood where wt-wt, wt-v, and v-v interactions determine selectivity, or on the tissue surface where tissue-wt and tissure-v interactions also determine selectivity. Statistical modeling in both cases thus involves selectivity in fibril aggregation and tissue binding. Because binding of protein molecules into fibrils and binding of fibrils to tissues occurs through multiple weak non-covalent bonds, strong complementarity between β-sheet molecules and between fibrils and tissues is required to explain the insolubility and tissue selectivity of ATTR amyloidosis. Observation of differing tissue selectivity and thence disease phenotypes from either pure wildtype TTR protein or a mix of wildtype and variant molecules in amyloid fibrils evidences the requirement for fibril-tissue complementarity. Understanding the process that forms fibrils and binds fibrils to tissues may lead to new possibilities for interrupting the process and preventing or curing ATTR amyloidosis.

Fig 1. Frequency of perfectly alternating fibrils assuming an odds ratio of 1.5 and equal concentrations of wt and v molecules.

Fig 2. Frequency of perfectly alternating fibrils assuming an odds ratio of 4 and equal concentrations of wt and v molecules.

Fig 3. The fraction of the 4096 possible combinations of 12 molecules that have a perfect repeating pattern of alternating wt and v molecules (blue) or have one error (red) as a function of the odds of an added molecule being the correct one.

The ratio wt:v is assumed to be 1:1.

Fig 4. The fraction of the 4096 possible combinations of 12 molecules that have a perfect repeating pattern of alternating wt and v molecules (blue) or have one error (red) as a function of the ratio v:wt.

The odds of adding the correct molecule is set at 4:1.

Fig 5. Interaction energies between wt and v molecules as a function of the “odds ratio” assumed in the statistical analysis of structured fibril formation.