Cell milieu significantly affects the fate of AApoAI amyloidogenic variants: predestination or serendipity?

Specific apolipoprotein A-I variants are associated to severe hereditary amyloidoses. The organ distribution of AApoAI amyloidosis seems to depend on the position of the mutation, since mutations in residues from 1 to 75 are mainly associated to hepatic and renal amyloidosis, while mutations in residues from 173 to 178 are mostly responsible for cardiac, laryngeal, and cutaneous amyloidosis. Molecular bases of this tissue specificity are still poorly understood, but it is increasingly emerging that protein destabilization induced by amyloidogenic mutations is neither necessary nor sufficient for amyloidosis development.

By using a multidisciplinary approach, including circular dichroism, dynamic light scattering, spectrofluorometric and atomic force microscopy analyses, the effect of target cells on the conformation and fibrillogenic pathway of the two AApoAI amyloidogenic variants AApoAI^L75P and AApoAI^L174S has been monitored.

Our data show that specific cell milieus selectively affect conformation, aggregation propensity and fibrillogenesis of the two AApoAI amyloidogenic variants.

An intriguing picture emerged indicating that defined cell contexts selectively induce fibrillogenesis of specific AApoAI variants.

An innovative methodological approach, based on the use of whole intact cells to monitor the effects of cell context on AApoAI variants fibrillogenic pathway, has been set up.