Familial Amyloidotic Polyneuropathy and Transthyretin

Abstract

There has been much progress in our understanding of transthyretin (TTR)-related amyloidosis including familial amyloidotic polyneuropathy (FAP), senile systemic amyloidosis and its related disorders from many clinical and experimental aspects. FAP is an inherited severe systemic amyloidosis caused by mutated TTR, and characterized by amyloid deposition mainly in the peripheral nervous system and the heart. Liver transplantation is the only available treatment for the disease. FAP is now recognized not to be a rare disease, and to have many variations based on genetical and biochemical variations of TTR. This chapter covers the recent advances in the clinical and pathological aspects of, and therapeutic approaches to FAP, and the trend as to the molecular pathogenesis of TTR.

Force spectroscopy reveals the presence of structurally modified dimers in transthyretin amyloid annular oligomers

“…To some extent the wild‐type form of TTR appears to be prone to amyloid aggregation as evidenced by cases of senile systemic amyloidosis where WT TTR is found in amyloid deposits . However, certain mutations in the TTR sequence can greatly enhance the process of aggregation even though no particular amyloidogenic hotspot can be assigned . In spite of this, in vitro aggregation of WT TTR and of most of its amyloidogenic variants is often induced by mild acidification, which has been proposed to mimic the lysosomal environment associated with the conversion of proteins and peptides into their amyloidogenic form .…”

“…7 However, certain mutations in the TTR sequence can greatly enhance the process of aggregation even though no particular amyloidogenic hotspot can be assigned. 1,8 In spite of this, in vitro aggregation of WT TTR and of most of its amyloidogenic variants is often induced by mild acidification, 9 which has been proposed to mimic the lysosomal environment associated with the conversion of proteins and peptides into their amyloidogenic form. [9][10][11] The resulting aggregates typically bind the amyloid markers Thioflavin-T and Congo red, 12,13 display a high content of β-sheets, 14 but lack the morphology of fibrils extracted from patient samples.…”