Transthyretin amyloidosis: a tale of weak interactions

Over 70 transthyretin (TTR) mutations have been associated with hereditary amyloidoses, which are all autosomal dominant disorders with adult age of o nset. TTR is the main constituent of amyloid that deposits preferentially i n peripheral nerve giving rise to familial amyloid polyneuropathy (FAP), or in the heart leading to familial amyloid cardiomyopathy. Since the beginni ng of this decade the central question of these types of amyloidoses has be en why TTR is an amyloidogenic protein with clinically heterogeneous pathog enic consequences. As a result of amino acid substitutions, conformational changes occur in the molecule, leading to weaker subunit interactions of th e tetrameric structure as revealed by X-ray studies of some amyloidogenic m utants. Modified soluble tetramers exposing cryptic epitopes seem to circul ate in FAP patients as evidenced by antibody probes recognizing specificall y TTR amyloid fibrils, but what triggers dissociation into monomeric and ol igomeric intermediates of amyloid fibrils is largely unknown. Avoiding tetr amer dissociation and disrupting amyloid fibrils are possible avenues of th erapeutic intervention based on current molecular knowledge of TTR amyloido genesis and fibril structure. (C) 2001 Federation of European Biochemical S ocieties. Published by Elsevier Science B,V, Ail rights reserved.