ABSTRACT
Amyloid fibril formation and deposition have been associated with a series of diseases, including Alzheimer’s, Spongiform encephalopathies, and several systemic amyloidosis. In most of these amyloid diseases, it has been shown that the normal precursor protein, due to proteolysis, mutation or molecular environment stress, undergoes misfolding, leading to molecular species with a high tendency for ordered aggregation into amyloid. Transthyretin (TTR) is a homotetrameric plasma protein with a high percentage of beta-sheet. TTR has been implicated in diseases such as Familial Amyloid Polyneuropathy and Senil Systemic Amyloidosis. The chapter proposes that compact denatured states may play a central role as amyloidogenic species, based on molecular dynamics unfolding simulations of TTR. Amyloid formation by TTR does not seem to be mediated by a local structural fluctuation or a local partial unfolding event, but by a global denaturing process of the subunit beta-sandwich.
