title: Pathogenesis of transthyretin amyloidosis.
abstract: Current dogma for transthyretin (TTR) pathogenesis is that mutations in TTR alter its structure such that the tetramer becomes unstable and prone to release of monomer which then becomes the putative building block of the fibril. This hypothesis is supported by thermodynamic data showing decreased stability of mutant TTR tetrameric proteins and accelerated fibril formation under acidic conditions in vitro. There are, however, a number of questions that are not readily answered by this simplistic model of a very complex disease. Worrisome questions still to be answered include: 1. If the monomer is the precursor of the fibril, why do fibril deposits contain large amounts of wild-type TTR and not just variant? 2. If destabilized tetramers can form fibrils in vitro, why do we consistently find partial proteolysis of fibril subunit proteins? If enzymatic proteolysis is a required step in fibril formation, are the findings of in vitro fibril formation relevant to the true pathogenesis? 3. With some TTR mutations (e.g. 122ΔVal), it would appear that very little TTR is present in the blood (probably due to degradation prior to hepatic secretion). Enough mutant TTR circulates to the heart and nerves to cause pathology but, if the mutant only serves to initiate fibril deposition, why are not the deposits mainly wild-type TTR?4. Since mutated TTR is present from birth, why is TTR amyloidosis of such delayed onset? What is the role of aging factors?5. Do the variations in biochemical analyses of heart and nerve versus choroid and leptomeningeal fibrils tell us something about pathogenesis? These are questions we need to address. Do not expect quick and easy answers. Hopefully, they will generate thought and discussion.
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Merrill D
authors.initials: MD
authors.lastname: Benson
mesh_terms: D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization
chemical_list: D011228:Prealbumin